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Sample records for growth promoting signaling

  1. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

    PubMed Central

    Harel, Sivan; Higgins, Claire A.; Cerise, Jane E.; Dai, Zhenpeng; Chen, James C.; Clynes, Raphael; Christiano, Angela M.

    2015-01-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells. PMID:26601320

  2. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.

    PubMed

    Harel, Sivan; Higgins, Claire A; Cerise, Jane E; Dai, Zhenpeng; Chen, James C; Clynes, Raphael; Christiano, Angela M

    2015-10-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells. PMID:26601320

  3. Two-signal requirement for growth-promoting function of Yap in hepatocytes

    PubMed Central

    Su, Tian; Bondar, Tanya; Zhou, Xu; Zhang, Cuiling; He, Hang; Medzhitov, Ruslan

    2015-01-01

    The transcriptional coactivator Yes-associated protein (Yap) promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. In this study, we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation, and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair. DOI: http://dx.doi.org/10.7554/eLife.02948.001 PMID:25667983

  4. Growth signaling promotes chronological aging in budding yeast by inducing superoxide anions that inhibit quiescence

    PubMed Central

    Weinberger, Martin; Mesquita, Ana; Carroll, Timothy; Marks, Laura; Yang, Hui; Zhang, Zhaojie; Ludovico, Paula; Burhans, William C.

    2010-01-01

    Inhibition of growth signaling pathways protects against aging and age-related diseases in parallel with reduced oxidative stress. The relationships between growth signaling, oxidative stress and aging remain unclear. Here we report that in Saccharomyces cerevisiae, alterations in growth signaling pathways impact levels of superoxide anions that promote chronological aging and inhibit growth arrest of stationary phase cells in G0/G1. Factors that decrease intracellular superoxide anions in parallel with enhanced longevity and more efficient G0/G1 arrest include genetic inactivation of growth signaling pathways that inhibit Rim15p, which activates oxidative stress responses, and downregulation of these pathways by caloric restriction. Caloric restriction also reduces superoxide anions independently of Rim15p by elevating levels of H2O2, which activates superoxide dismutases. In contrast, high glucose or mutations that activate growth signaling accelerate chronological aging in parallel with increased superoxide anions and reduced efficiency of stationary phase G0/G1 arrest. High glucose also activates DNA damage responses and preferentially kills stationary phase cells that fail to arrest growth in G0/G1. These findings suggest that growth signaling promotes chronological aging in budding yeast by elevating superoxide anions that inhibit quiescence and induce DNA replication stress. A similar mechanism likely contributes to aging and age-related diseases in complex eukaryotes. PMID:21076178

  5. TOR Signaling Promotes Accumulation of BZR1 to Balance Growth with Carbon Availability in Arabidopsis.

    PubMed

    Zhang, Zhenzhen; Zhu, Jia-Ying; Roh, Jeehee; Marchive, Chloé; Kim, Seong-Ki; Meyer, Christian; Sun, Yu; Wang, Wenfei; Wang, Zhi-Yong

    2016-07-25

    For maintenance of cellular homeostasis, the actions of growth-promoting hormones must be attenuated when nutrient and energy become limiting. The molecular mechanisms that coordinate hormone-dependent growth responses with nutrient availability remain poorly understood in plants [1, 2]. The target of rapamycin (TOR) kinase is an evolutionarily conserved master regulator that integrates nutrient and energy signaling to regulate growth and homeostasis in both animals and plants [3-7]. Here, we show that sugar signaling through TOR controls the accumulation of the brassinosteroid (BR)-signaling transcription factor BZR1, which is essential for growth promotion by multiple hormonal and environmental signals [8-11]. Starvation, caused by shifting of light-grown Arabidopsis seedlings into darkness, as well as inhibition of TOR by inducible RNAi, led to plant growth arrest and reduced expression of BR-responsive genes. The growth arrest caused by TOR inactivation was partially recovered by BR treatment and the gain-of-function mutation bzr1-1D, which causes accumulation of active forms of BZR1 [12]. Exogenous sugar promoted BZR1 accumulation and seedling growth, but such sugar effects were largely abolished by inactivation of TOR, whereas the effect of TOR inactivation on BZR1 degradation is abolished by inhibition of autophagy and by the bzr1-1D mutation. These results indicate that cellular starvation leads sequentially to TOR inactivation, autophagy, and BZR1 degradation. Such regulation of BZR1 accumulation by glucose-TOR signaling allows carbon availability to control the growth promotion hormonal programs, ensuring supply-demand balance in plant growth. PMID:27345161

  6. Epidermal growth factor promotes proliferation of dermal papilla cells via Notch signaling pathway.

    PubMed

    Zhang, Haihua; Nan, Weixiao; Wang, Shiyong; Zhang, Tietao; Si, Huazhe; Wang, Datao; Yang, Fuhe; Li, Guangyu

    2016-08-01

    The effect of epidermal growth factor (EGF) on the development and growth of hair follicle is controversial. In the present study, 2-20 ng/ml EGF promoted the growth of mink hair follicles in vitro, whereas 200 ng/ml EGF inhibited follicle growth. Further, dermal papilla (DP) cells, a group of mesenchymal cells that govern hair follicle development and growth, were isolated and cultured in vitro. Treatment with or forced expression of EGF accelerated proliferation and induced G1/S transition in DP cells. Moreover, EGF upregulated the expression of DP mesenchymal genes, such as alkaline phosphatase (ALP) and insulin-like growth factor (IGF-1), as well as the Notch pathway molecules including Notch1, Jagged1, Hes1 and Hes5. In addition, inhibition of Notch signaling pathway by DAPT significantly reduced the basal and EGF-enhanced proliferation rate, and also suppressed cell cycle progression. We also show that the expression of several follicle-regulatory genes, such as Survivin and Msx2, were upregulated by EGF, and was inhibited by DAPT. In summary, our study demonstrates that the concentration of EGF is critical for the switch between hair follicle growth and inhibition, and EGF promotes DP cell proliferation via Notch signaling pathway. PMID:27109378

  7. Protopanaxatirol type ginsenoside Re promotes cyclic growth of hair follicles via inhibiting transforming growth factor β signaling cascades.

    PubMed

    Li, Zheng; Ryu, Seung-Wook; Lee, Jungsul; Choi, Kyungsun; Kim, Sunchang; Choi, Chulhee

    2016-02-19

    Ginsenosides, the major bio-active ingredients included in Panax ginseng, have been known for the hair growth activity and used to treat patients who suffer from hair loss; however, the detailed mechanisms of this action are still largely unknown. This study was conducted to investigate the molecular and cellular mechanisms responsible for hair growth promoting effect of ginsenoside Re (GRe) in vitro and in vivo. Different doses of minoxidil and GRe were administered topically to the back regions of nude mice for up to 45 days, and hair shaft length and hair cycles were determined for hair promoting activities. Topical treatment of GRe significantly increased the hair shaft length and hair existent time, which was comparable to the action of minoxidil. We also demonstrated that GRe stimulated hair shaft elongation in the ex vivo cultures of vibrissa hair follicles isolated from C57BL/6 mouse. Systemic transcriptome analysis by next generation sequencing demonstrated that TGF-β-pathway related genes were selectively down-regulated by treatment of GRe in vivo, and the same treatment suppressed TGF-β-induced phosphorylation of ERK in HeLa cells. The results clearly indicated that GRe is the effective constituent in the ginseng on hair promotion via selective inhibition of the hair growth phase transition related signaling pathways, TGF-β signaling cascades. PMID:26820528

  8. Drosophila Vps4 promotes Epidermal growth factor receptor signaling independently of its role in receptor degradation

    PubMed Central

    Legent, Kevin; Liu, Hui Hua; Treisman, Jessica E.

    2015-01-01

    Endocytic trafficking of signaling receptors is an important mechanism for limiting signal duration. Components of the Endosomal Sorting Complexes Required for Transport (ESCRT), which target ubiquitylated receptors to intra-lumenal vesicles (ILVs) of multivesicular bodies, are thought to terminate signaling by the epidermal growth factor receptor (EGFR) and direct it for lysosomal degradation. In a genetic screen for mutations that affect Drosophila eye development, we identified an allele of Vacuolar protein sorting 4 (Vps4), which encodes an AAA ATPase that interacts with the ESCRT-III complex to drive the final step of ILV formation. Photoreceptors are largely absent from Vps4 mutant clones in the eye disc, and even when cell death is genetically prevented, the mutant R8 photoreceptors that develop fail to recruit surrounding cells to differentiate as R1-R7 photoreceptors. This recruitment requires EGFR signaling, suggesting that loss of Vps4 disrupts the EGFR pathway. In imaginal disc cells mutant for Vps4, EGFR and other receptors accumulate in endosomes and EGFR target genes are not expressed; epistasis experiments place the function of Vps4 at the level of the receptor. Surprisingly, Vps4 is required for EGFR signaling even in the absence of Shibire, the Dynamin that internalizes EGFR from the plasma membrane. In ovarian follicle cells, in contrast, Vps4 does not affect EGFR signaling, although it is still essential for receptor degradation. Taken together, these findings indicate that Vps4 can promote EGFR activity through an endocytosis-independent mechanism. PMID:25790850

  9. TGF-β signaling deficient fibroblasts enhance Hepatocyte Growth Factor signaling in mammary carcinoma cells to promote scattering and invasion

    PubMed Central

    Cheng, Nikki; Chytil, Anna; Shyr, Yu; Joly, Alison; Moses, Harold L.

    2009-01-01

    Fibroblasts are major cellular components of the tumor microenvironment, regulating tumor cell behavior in part through secretion of extracellular matrix proteins, growth factors and angiogenic factors. In previous studies, conditional deletion of the type II TGF-β receptor in fibroblasts (Tgfbr2FspKO) was shown to promote mammary tumor metastasis in fibroblast: epithelial cell co-transplantation studies in mice, correlating with increased expression of HGF. Here, we advance our findings to show that Tgfbr2FspKO fibroblasts enhance HGF/c-Met and HGF/Ron signaling to promote scattering and invasion of mammary carcinoma cells. Blockade of c-Met and Ron by siRNA silencing and pharmacologic inhibitors significantly reduced mammary carcinoma cell scattering and invasion caused by Tgfbr2FspKO fibroblasts. Moreover, neutralizing antibodies to c-Met and Ron significantly inhibited HGF-induced cell scattering and invasion correlating with reduced Stat3 and p42/44MAPK phosphorylation. Investigation of the Stat3 and MAPK signaling pathways by pharmacologic inhibition and siRNA silencing revealed a cooperative interaction between the two pathways to regulate HGF- induced invasion, scattering and motility of mammary tumor cells. Furthermore, while c-Met was found to regulate both the Stat3 and MAPK signaling pathways, Ron was found to regulate Stat3, but not MAPK signaling in mammary carcinoma cells. These studies demonstrate a tumor suppressive role for TGF-β signaling in fibroblasts, in part by suppressing HGF signaling between mammary fibroblasts and epithelial cells. These studies characterize complex functional roles for HGF and TGF-β signaling in mediating tumor: stromal interactions during mammary tumor cell scattering and invasion, with important implications in the metastatic process. PMID:18922968

  10. Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling.

    PubMed

    Hu, Bin; Nandhu, Mohan S; Sim, Hosung; Agudelo-Garcia, Paula A; Saldivar, Joshua C; Dolan, Claire E; Mora, Maria E; Nuovo, Gerard J; Cole, Susan E; Viapiano, Mariano S

    2012-08-01

    Malignant gliomas are highly invasive and chemoresistant brain tumors with extremely poor prognosis. Targeting of the soluble factors that trigger invasion and resistance, therefore, could have a significant impact against the infiltrative glioma cells that are a major source of recurrence. Fibulin-3 is a matrix protein that is absent in normal brain but upregulated in gliomas and promotes tumor invasion by unknown mechanisms. Here, we show that fibulin-3 is a novel soluble activator of Notch signaling that antagonizes DLL3, an autocrine inhibitor or Notch, and promotes tumor cell survival and invasion in a Notch-dependent manner. Using a strategy for inducible knockdown, we found that controlled downregulation of fibulin-3 reduced Notch signaling and led to increased apoptosis, reduced self-renewal of glioblastoma-initiating cells, and impaired growth and dispersion of intracranial tumors. In addition, fibulin-3 expression correlated with expression levels of Notch-dependent genes and was a marker of Notch activation in patient-derived glioma samples. These findings underscore a major role for the tumor extracellular matrix in regulating glioma invasion and resistance to apoptosis via activation of the key Notch pathway. More importantly, this work describes a noncanonical, soluble activator of Notch in a cancer model and shows how Notch signaling can be reduced by targeting tumor-specific accessible molecules in the tumor microenvironment. PMID:22665268

  11. URG11 promotes gastric cancer growth and invasion by activation of β-catenin signalling pathway

    PubMed Central

    Du, Rui; Xia, Lin; Sun, Shiren; Lian, Zhaorui; Zou, Xue; Gao, Juan; Xie, Huahong; Fan, Rui; Song, Jiugang; Li, Xiaohua; Liu, Jie; Fan, Daiming

    2010-01-01

    Abstract Upregulated gene 11 (URG11), a new gene upregulated by Heptatitis B Virus X protein (HBx), was previously shown to activate β-catenin and promote hepatocellular growth and tumourigenesis. Although the oncogenic role of URG11 in the development of hepatocellular carcinoma has been well documented, its relevance to other human malignancies and the underlying molecular mechanisms remain largely unknown. Here we reported a novel function of URG11 to promote gastric cancer growth and metastasis. URG11 was found to be highly expressed in gastric cancer tissues compared with adjacent nontumourous ones by immunohistochemical staining and western blot. Knockdown of URG11 expression by small interfering RNA (siRNA) effectively attenuated the proliferation, anchorage-independent growth, invasiveness and metastatic potential of gastric cancer cells. URG11 inhibition led to decreased expression of β-catenin and its nuclear accumulation in gastric cancer cells and extensive costaining between URG11 and β-catenin was observed in gastric cancer tissues. Transient transfection assays with the β-catenin promoter showed that it was inhibited by URG11-specific small inhibitory RNA. Moreover, suppression of endogenous URG11 expression results in decreased activation of β-catenin/TCF and its downstream effector genes, cyclinD1 and membrane type 1 matrix metallopeptidase (MT1-MMP), which are known to be involved in cell proliferation and invasion, respectively. Taken together, our data suggest that URG11 contributes to gastric cancer growth and metastasis at least partially through activation of β-catenin signalling pathway. These findings also propose a promising target for gene therapy in gastric cancer. PMID:19413886

  12. Rhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway

    PubMed Central

    Song, Wei; Liu, Wenjie; Zhao, Hong; Li, Shangze; Guan, Xin; Ying, Jianming; Zhang, Yefan; Miao, Fei; Zhang, Mengmeng; Ren, Xiaoxia; Li, Xiaolu; Wu, Fan; Zhao, Yuechao; Tian, Yuanyuan; Wu, Wenming; Fu, Jun; Liang, Junbo; Wu, Wei; Liu, Changzheng; Yu, Jia; Zong, Shudong; Miao, Shiying; Zhang, Xiaodong; Wang, Linfang

    2015-01-01

    Rhomboid proteins perform a wide range of important functions in a variety of organisms. Recent studies have revealed that rhomboid proteins are involved in human cancer progression; however, the underlying molecular mechanism remains largely unclear. Here we show that RHBDD1, a rhomboid intramembrane serine protease, is highly expressed and closely associated with survival in patients with colorectal cancer. We observe that inactivation of RHBDD1 decreases tumor cell growth. Further studies show that RHBDD1 interacts with proTGFα and induces the ADAM-independent cleavage and secretion of proTGFα. The secreted TGFα further triggers the activation of the EGFR/Raf/MEK/ERK signalling pathway. Finally, the positive correlation of RHBDD1 expression with the EGFR/Raf/MEK/ERK signalling pathway is further corroborated in a murine model of colitis-associated colorectal cancer. These findings provide evidence of a growth-promoting role for RHBDD1 in colorectal cancer and may aid the development of tumor biomarkers or antitumor therapeutics. PMID:26300397

  13. Fetuin-A promotes primary keratinocyte migration: independent of epidermal growth factor receptor signalling.

    PubMed

    Wang, Xue-Qing; Hung, Betsy S; Kempf, Margit; Liu, Pei-Yun; Dalley, Andrew J; Saunders, Nicholas A; Kimble, Roy M

    2010-08-01

    Previously, we reported that fetuin-A is a major component of ovine foetal skin and significantly enhances 'wound closure' in primary keratinocyte cultures. In this study, we found that in human newborn foreskin, a high level of fetuin-A protein is detected throughout the dermis. However, in adult skin a low level of fetuin-A is observed throughout the epidermal and dermal layers, except at regions surrounding hair follicles and at the epidermal-dermal junction where the level of fetuin-A is relatively high. Fetuin-A significantly induces actin-rich protrusions in human primary keratinocytes. Interestingly, blockade of epidermal growth factor (EGF) receptor signalling has a limited effect on fetuin-A promoted 'wound closure' on primary human keratinocytes, but significantly inhibits fetuin-A's effect on HaCaT cells. These results indicate that high levels of fetuin-A may partially contribute to less scar formation in newborn foreskin and that the effect of fetuin-A on primary keratinocyte migration is independent of EGF receptor signalling. PMID:19758338

  14. Antibody-mediated inhibition of Nogo-A signaling promotes neurite growth in PC-12 cells

    PubMed Central

    Yazdi, Iman K; Taghipour, Nima; Hmaidan, Sarah; Palomba, Roberto; Scaria, Shilpa; Munoz, Alvaro; Boone, Timothy B; Tasciotti, Ennio

    2016-01-01

    The use of a monoclonal antibody to block the neurite outgrowth inhibitor Nogo-A has been of great interest for promoting axonal recovery as a treatment for spinal cord injury. While several cellular and non-cellular assays have been developed to quantify the bioactive effects of Nogo-A signaling, demand still exists for the development of a reliable approach to characterize the effectiveness of the anti-Nogo-A antibody. In this study, we developed and validated a novel cell-based approach to facilitate the biological quantification of a Nogo-A antibody using PC-12 cells as an in vitro neuronal cell model. Changes in the mRNA levels of the neuronal differentiation markers, growth-associated protein 43 and neurofilament light-polypeptide, suggest that activation of the Nogo-A pathway suppresses axonal growth and dendrite formation in the tested cell line. We found that application of anti-Nogo-A monoclonal antibody can significantly enhance the neuronal maturity of PC-12 cells by blocking the Nogo-A inhibitory effects, providing enhanced effects on neural maturity at the molecular level. No adverse effects were observed on cell viability. PMID:27027860

  15. Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway

    PubMed Central

    Kwan, Hiu Yee; Fu, Xiuqiong; Liu, Bin; Chao, Xiaojuan; Chan, Chi Leung; Cao, Huihui; Su, Tao; Tse, Anfernee Kai Wing; Fong, Wang Fun; Yu, Zhi-Ling

    2014-01-01

    Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY® FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt. PMID:25228694

  16. GAP-43 promoter elements in transgenic zebrafish reveal a difference in signals for axon growth during CNS development and regeneration.

    PubMed

    Udvadia, A J; Köster, R W; Skene, J H

    2001-04-01

    A pivotal event in neural development is the point at which differentiating neurons become competent to extend long axons. Initiation of axon growth is equally critical for regeneration. Yet we have a limited understanding of the signaling pathways that regulate the capacity for axon growth during either development or regeneration. Expression of a number of genes encoding growth associated proteins (GAPs) accompanies both developmental and regenerative axon growth and has led to the suggestion that the same signaling pathways regulate both modes of axon growth. We have tested this possibility by asking whether a promoter fragment from a well characterized GAP gene, GAP-43, is sufficient to activate expression in both developing and regenerating neurons. We generated stable lines of transgenic zebrafish that express green fluorescent protein (GFP) under regulation of a 1 kb fragment of the rat GAP-43 gene, a fragment that contains a number of evolutionarily conserved elements. Analysis of GFP expression in these lines confirms that the rat 1 kb region can direct growth-associated expression of the transgene in differentiating neurons that extend long axons. Furthermore, this region supports developmental down-regulation of transgene expression which, like the endogenous gene, coincides with neuronal maturation. Strikingly, these same sequences are insufficient for directing expression in regenerating neurons. This finding suggests that signaling pathways regulating axon growth during development and regeneration are not the same. While these results do not exclude the possibility that pathways involved in developmental axon growth are also active in regenerative growth, they do indicate that signaling pathway(s) controlling activation of the GAP-43 gene after CNS injury differ in at least one key component from the signals controlling essential features of developmental axon growth. PMID:11245583

  17. Root ethylene signalling is involved in Miscanthus sinensis growth promotion by the bacterial endophyte Herbaspirillum frisingense GSF30T

    PubMed Central

    Ludewig, Uwe

    2013-01-01

    The bacterial endophyte Herbaspirillum frisingense GSF30T is a colonizer of several grasses grown in temperate climates, including the highly nitrogen-efficient perennial energy grass Miscanthus. Inoculation of Miscanthus sinensis seedlings with H. frisingense promoted root and shoot growth but had only a minor impact on nutrient concentrations. The bacterium affected the root architecture and increased fine-root structures. Although H. frisingense has the genetic requirements to fix nitrogen, only minor changes in nitrogen concentrations were observed. Herbaspirillum agglomerates were identified primarily in the root apoplast but also in the shoots. The short-term (3h) and long-term (3 weeks) transcriptomic responses of the plant to bacterial inoculation revealed that H. frisingense induced rapid changes in plant hormone signalling, most prominent in jasmonate signalling. Ethylene signalling pathways were also affected and persisted after 3 weeks in the root. Growth stimulation of the root by the ethylene precursor 1-aminocyclopropane 1-carboxylic acid was dose dependent and was affected by H. frisingense inoculation. Minor changes in the proteome were identified after 3 weeks. This study suggests that H. frisingense improves plant growth by modulating plant hormone signalling pathways and provides a framework to understand the beneficial effects of diazotrophic plant-growth-promoting bacteria, such as H. frisingense, on the biomass grass Miscanthus. PMID:24043849

  18. Root-Shoot Signaling crosstalk involved in the shoot growth promoting action of rhizospheric humic acids

    PubMed Central

    Olaetxea, Maite; Mora, Verónica; García, Andrés Calderin; Santos, Leandro Azevedo; Baigorri, Roberto; Fuentes, Marta; Garnica, María; Berbara, Ricardo Luis Louro; Zamarreño, Angel Maria; Garcia-Mina, Jose M.

    2016-01-01

    ABSTRACT Numerous studies have shown the ability of humic substances to improve plant development. This action is normally reflected in an enhancement of crop yields and quality. However, the mechanisms responsible for this action of humic substances remain rather unknown. Our studies have shown that the shoot promoting action of sedimentary humic acids is dependent of its ability to increase root hydraulic conductivity through signaling pathways related to ABA, which in turn is affected in roots by humic acids in an IAA-NO dependent way. Furthermore, these studies also indicate that the primary action of humic acids in roots might also be physical, resulting from a transient mild stress caused by humic acids associated with a fouling-cleaning cycle of wall cell pores. Finally the role of alternative signal molecules, such as ROS, and corresponding signaling pathways are also discussed and modeled in the context of the above-mentioned framework. PMID:26966789

  19. Epsin 1 Promotes Synaptic Growth by Enhancing BMP Signal Levels in Motoneuron Nuclei

    PubMed Central

    Chastain, Lerin R.; Royer, Suzanne M.; Bao, Hong; Reist, Noreen E.; Zhang, Bing

    2013-01-01

    Bone morphogenetic protein (BMP) retrograde signaling is crucial for neuronal development and synaptic plasticity. However, how the BMP effector phospho-Mother against decapentaplegic (pMad) is processed following receptor activation remains poorly understood. Here we show that Drosophila Epsin1/Liquid facets (Lqf) positively regulates synaptic growth through post-endocytotic processing of pMad signaling complex. Lqf and the BMP receptor Wishful thinking (Wit) interact genetically and biochemically. lqf loss of function (LOF) reduces bouton number whereas overexpression of lqf stimulates bouton growth. Lqf-stimulated synaptic overgrowth is suppressed by genetic reduction of wit. Further, synaptic pMad fails to accumulate inside the motoneuron nuclei in lqf mutants and lqf suppresses synaptic overgrowth in spinster (spin) mutants with enhanced BMP signaling by reducing accumulation of nuclear pMad. Interestingly, lqf mutations reduce nuclear pMad levels without causing an apparent blockage of axonal transport itself. Finally, overexpression of Lqf significantly increases the number of multivesicular bodies (MVBs) in the synapse whereas lqf LOF reduces MVB formation, indicating that Lqf may function in signaling endosome recycling or maturation. Based on these observations, we propose that Lqf plays a novel endosomal role to ensure efficient retrograde transport of BMP signaling endosomes into motoneuron nuclei. PMID:23840387

  20. Decoction and Fermentation of Selected Medicinal Herbs Promote Hair Regrowth by Inducing Hair Follicle Growth in Conjunction with Wnts Signaling.

    PubMed

    Jang, Su Kil; Kim, Seung Tae; Lee, Do Ik; Park, Jun Sub; Jo, Bo Ram; Park, Jung Youl; Heo, Jong; Joo, Seong Soo

    2016-01-01

    It is well recognized that regulating the hair follicle cycle in association with Wnt signaling is one of the most interesting targets for promoting hair regrowth. In this study, we examined whether selected herbal medicines processed by decoction and fermentation promote hair growth by upregulating the number and size of hair follicles and Wnt signaling, including activation of β-catenin and Akt in telogen-synchronized C57BL/6N mice. The results revealed that the fermented extract after decoction (FDE) more effectively promoted hair growth than that of a nonfermented extract (DE). Notably, FDE effectively enhanced formation of hair follicles with clearer differentiation between the inner and outer root sheath, which is observed during the anagen phase. Mechanistic evidence was found for increased β-catenin and Akt phosphorylation levels in dorsal skin tissue along with elevated expression of hair regrowth-related genes, such as Wnt3/10a/10b, Lef1, and fibroblast growth factor 7. In conclusion, our findings suggest that FDE plays an important role in regulating the hair cycle by increasing expression of hair regrowth-related genes and activating downstream Wnt signaling targets. PMID:27110266

  1. Decoction and Fermentation of Selected Medicinal Herbs Promote Hair Regrowth by Inducing Hair Follicle Growth in Conjunction with Wnts Signaling

    PubMed Central

    Jang, Su Kil; Kim, Seung Tae; Lee, Do Ik; Park, Jun Sub; Jo, Bo Ram; Park, Jung Youl; Heo, Jong; Joo, Seong Soo

    2016-01-01

    It is well recognized that regulating the hair follicle cycle in association with Wnt signaling is one of the most interesting targets for promoting hair regrowth. In this study, we examined whether selected herbal medicines processed by decoction and fermentation promote hair growth by upregulating the number and size of hair follicles and Wnt signaling, including activation of β-catenin and Akt in telogen-synchronized C57BL/6N mice. The results revealed that the fermented extract after decoction (FDE) more effectively promoted hair growth than that of a nonfermented extract (DE). Notably, FDE effectively enhanced formation of hair follicles with clearer differentiation between the inner and outer root sheath, which is observed during the anagen phase. Mechanistic evidence was found for increased β-catenin and Akt phosphorylation levels in dorsal skin tissue along with elevated expression of hair regrowth-related genes, such as Wnt3/10a/10b, Lef1, and fibroblast growth factor 7. In conclusion, our findings suggest that FDE plays an important role in regulating the hair cycle by increasing expression of hair regrowth-related genes and activating downstream Wnt signaling targets. PMID:27110266

  2. Epigenetic silencing of NKD2, a major component of Wnt signaling, promotes breast cancer growth

    PubMed Central

    Dong, Yan; Cao, Baoping; Zhang, Meiying; Han, Weidong; Herman, James G.; Fuks, François; Zhao, Yali; Guo, Mingzhou

    2015-01-01

    Naked cuticle homolog 2 (NKD2) has been reported to antagonize Wnt signaling in zebrafish, mouse and mammals. The aim of this study is to investigate the epigenetic changes and mechanisms of NKD2 in human breast cancer development. Six breast cancer cell lines (MCF-7, ZR75-1, MDA-MB-468, MDA-MB-231, T47D and BT474) and 68 cases of primary human breast cancer were studied using methylation specific PCR, immunohistochemistry, western blot, flow cytometry techniques and a xenograft mouse model. The expression of NKD1 and NKD2 was regulated by promoter region methylation in breast cancer cells. No NKD1 methylation was found in primary human breast cancer. NKD2 was methylated in 51.4% (35/68) of human primary breast cancer samples. NKD2 methylation was significantly associated with reduction of NKD2 expression, and tumor stage (p < 0.05). NKD2 suppressed breast cancer cell proliferation both in vitro and in vivo. NKD2 induced G1/S arrest and inhibited Wnt signaling in breast cancer cells. In conclusion, NKD2 is frequently methylated in human breast cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses breast cancer proliferation by inhibiting Wnt signaling. PMID:26124080

  3. SOXC Transcription Factors Induce Cartilage Growth Plate Formation in Mouse Embryos by Promoting Noncanonical WNT Signaling.

    PubMed

    Kato, Kenji; Bhattaram, Pallavi; Penzo-Méndez, Alfredo; Gadi, Abhilash; Lefebvre, Véronique

    2015-09-01

    Growth plates are specialized cartilage structures that ensure the elongation of most skeletal primordia during vertebrate development. They are made by chondrocytes that proliferate in longitudinal columns and then progress in a staggered manner towards prehypertrophic, hypertrophic and terminal maturation. Complex molecular networks control the formation and activity of growth plates, but remain incompletely understood. We investigated here the importance of the SoxC genes, which encode the SOX4, SOX11 and SOX12 transcription factors, in growth plates. We show that the three genes are expressed robustly in perichondrocytes and weakly in growth plate chondrocytes. SoxC(Prx1Cre) mice, which deleted SoxC genes in limb bud skeletogenic mesenchyme, were born with tiny appendicular cartilage primordia because of failure to form growth plates. In contrast, SoxC(Col2Cre) and SoxC(ATC) mice, which deleted SoxC genes primarily in chondrocytes, were born with mild dwarfism and fair growth plates. Chondrocytes in the latter mutants matured normally, but formed irregular columns, proliferated slowly and died ectopically. Asymmetric distribution of VANGL2 was defective in both SoxC(Prx1Cre) and SoxC(ATC) chondrocytes, indicating impairment of planar cell polarity, a noncanonical WNT signaling pathway that controls growth plate chondrocyte alignment, proliferation and survival. Accordingly, SoxC genes were necessary in perichondrocytes for expression of Wnt5a, which encodes a noncanonical WNT ligand required for growth plate formation, and in chondrocytes and perichondrocytes for expression of Fzd3 and Csnk1e, which encode a WNT receptor and casein kinase-1 subunit mediating planar cell polarity, respectively. Reflecting the differential strengths of the SOXC protein transactivation domains, SOX11 was more powerful than SOX4, and SOX12 interfered with the activity of SOX4 and SOX11. Altogether, these findings provide novel insights into the molecular regulation of skeletal

  4. N-docosahexaenoylethanolamine regulates Hedgehog signaling and promotes growth of cortical axons

    PubMed Central

    Kharebava, Giorgi; Rashid, Mohammad A.; Lee, Ji-Won; Sarkar, Sarmila; Kevala, Karl; Kim, Hee-Yong

    2015-01-01

    ABSTRACT Axonogenesis, a process for the establishment of neuron connectivity, is central to brain function. The role of metabolites derived from docosahexaenoic acid (DHA, 22:6n-3) that is specifically enriched in the brain, has not been addressed in axon development. In this study, we tested if synaptamide (N-docosahexaenoylethanolamine), an endogenous metabolite of DHA, affects axon growth in cultured cortical neurons. We found that synaptamide increased the average axon length, inhibited GLI family zinc finger 1 (GLI1) transcription and sonic hedgehog (Shh) target gene expression while inducing cAMP elevation. Similar effects were produced by cyclopamine, a regulator of the Shh pathway. Conversely, Shh antagonized elevation of cAMP and blocked synaptamide-mediated increase in axon length. Activation of Shh pathway by a smoothened (SMO) agonist (SAG) or overexpression of SMO did not inhibit axon growth mediated by synaptamide or cyclopamine. Instead, adenylate cyclase inhibitor SQ22536 abolished synaptamide-mediated axon growth indicating requirement of cAMP elevation for this process. Our findings establish that synaptamide promotes axon growth while Shh antagonizes synaptamide-mediated cAMP elevation and axon growth by a SMO-independent, non-canonical pathway. PMID:26545965

  5. The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling.

    PubMed

    Birdsey, Graeme M; Shah, Aarti V; Dufton, Neil; Reynolds, Louise E; Osuna Almagro, Lourdes; Yang, Youwen; Aspalter, Irene M; Khan, Samia T; Mason, Justin C; Dejana, Elisabetta; Göttgens, Berthold; Hodivala-Dilke, Kairbaan; Gerhardt, Holger; Adams, Ralf H; Randi, Anna M

    2015-01-12

    Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS transcription factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (Erg(cEC-KO)) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (Erg(iEC-KO)) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in Erg(cEC-KO) embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling. PMID:25584796

  6. Fas signal promotes lung cancer growth by recruiting myeloid-derived suppressor cells via cancer cell-derived PGE2.

    PubMed

    Zhang, Yongliang; Liu, Qiuyan; Zhang, Minggang; Yu, Yizhi; Liu, Xia; Cao, Xuetao

    2009-03-15

    Fas/FasL system has been extensively investigated with respect to its capacity to induce cellular apoptosis. However, accumulated evidences show that Fas signaling also exhibits nonapoptotic functions, such as induction of cell proliferation and differentiation. Lung cancer is one of cancer's refractory to the immunotherapy, however, the underlying mechanisms remain to be fully understood. In this study, we show that Fas overexpression does not affect in vitro growth of 3LL cells, but promotes lung cancer growth in vivo. However, such tumor-promoting effect is not observed in FasL-deficient (gld) mice, and also not observed in the immune competent mice once inoculation with domain-negative Fas-overexpressing 3LL cells, suggesting the critical role of Fas signal in the promotion of lung cancer growth in vivo. More accumulation of myeloid-derived suppressor cells (MDSC) and Foxp3(+) regulatory T cells is found in tumors formed by inoculation with Fas-overexpressing 3LL cells, but not domain-negative Fas-overexpressing 3LL cells. Accordingly, Fas-ligated 3LL lung cancer cells can chemoattract more MDSC but not regulatory T cells in vitro. Furthermore, Fas ligation induces 3LL lung cancer cells to produce proinflammatory factor PGE(2) by activating p38 pathway, and in turn, 3LL cells-derived PGE(2) contribute to the Fas ligation-induced MDSC chemoattraction. Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor. Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE(2), thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape. PMID:19265159

  7. Sonic hedgehog signaling promotes growth of oral squamous cell carcinoma cells associated with bone destruction.

    PubMed

    Honami, Tatsuki; Shimo, Tsuyoshi; Okui, Tatsuo; Kurio, Naito; Hassan, Nur Mohammad Monsur; Iwamoto, Masahiro; Sasaki, Akira

    2012-01-01

    Sonic hedgehog (Shh) and its signaling have been identified in several human cancers, and increased levels of its expression appear to correlate with disease progression and metastasis. However, the role of Shh in bone destruction associated with oral squamous cell carcinomas, which frequently invade the maxilla or the mandible, is still unclear. In this study we show that the use of siRNA for Shh to block SHH secreted by SAS oral squamous cell carcinoma cells suppressed the tumor growth and tumor angiogenesis of subcutaneous SAS xenografts in vivo. Moreover, blockade of Shh in SAS cells decreased tumor growth and osteoclast number in a tibial metaphysis mouse model. Significantly, we clearly show that SHH stimulated osteoclast formation in a co-culture system consisting of murine bone stromal ST2 cells and murine CD11b(+) bone marrow cells. These findings suggest that Shh signaling is a potential target for the treatment of oral squamous cell carcinoma associated with bone destruction. PMID:21945071

  8. Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis

    PubMed Central

    Takagi, Satoshi; Takemoto, Ai; Takami, Miho; Oh-hara, Tomoko; Fujita, Naoya

    2014-01-01

    The interactions of tumor cells with platelets contribute to the progression of tumor malignancy, and the expression levels of platelet aggregation-inducing factors positively correlate with the metastatic potential of osteosarcoma cells. However, it is unclear how tumor-platelet interaction contributes to the proliferation of osteosarcomas. We report here that osteosarcoma-platelet interactions induce the release of platelet-derived growth factor (PDGF) from platelets, which promotes the proliferation of osteosarcomas. Co-culture of platelets with MG63 or HOS osteosarcoma cells, which could induce platelet aggregation, enhanced the proliferation of each cell line in vitro. Analysis of phospho-antibody arrays revealed that co-culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor (PDGFR) and Akt. The addition of supernatants of osteosarcoma-platelet reactants also increased the growth of MG63 and HOS cells as well as the level of phosphorylated-PDGFR and -Akt. Sunitinib or LY294002, but not erlotinib, significantly inhibited the platelet-induced proliferation of osteosarcoma cells, indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the PDGFR and then Akt. Our results suggest that inhibitors that specifically target osteosarcoma-platelet interactions may eradicate osteosarcomas. PMID:24974736

  9. HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling

    PubMed Central

    Xue, Xiang; Jungles, Kylie; Onder, Gunseli; Samhoun, Jalal; Győrffy, Balázs; Hardiman, Karin M.

    2016-01-01

    Hypoxic environment is critical in colorectal cancer (CRC) development. Most studies have mainly focused on hypoxia-inducible factor (HIF)-1α and HIF-2α as the major hypoxic transcription factors in CRC development and progression. However, the role of HIF-3α in CRC is not clear. Here we found that HIF-3α protein was increased in colorectal tumors from both mouse models and human patients. Moreover, increased HIF-3α expression was correlated with decreased survival. Overexpression of a long isoform of HIF-3α, HIF-3α1, increased cell growth in two CRC cell lines. Surprisingly, overexpressed HIF-3α1 was localized to the cytosol and increased phosphorylated signal transducer and activator of transcription 3 (p-STAT3). STAT3 inhibition effectively reduced p-STAT3 levels and cell growth induced by HIF-3α1. The activation of p-STAT3 was independent of the transcriptional activity of HIF-3α1. However, the inhibition of the upstream regulator Janus kinase (JAK) abolished HIF-3α1-induced p-STAT3 and cell growth. Together, these results demonstrated that HIF-3α1 promotes CRC cell growth by activation of the JAK-STAT3 signaling pathway through non-canonical transcription-independent mechanisms. PMID:26871465

  10. Id-1 promotes osteosarcoma cell growth and inhibits cell apoptosis via PI3K/AKT signaling pathway.

    PubMed

    Hao, Liang; Liao, Qi; Tang, Qiang; Deng, Huan; Chen, Lu

    2016-02-12

    Accumulating evidence reveals that Id-1 is upregulated and functions as a potential tumor promoter in several human cancer types. However, the role of Id-1 in osteosarcoma (OS) is unknown. In present study, we found that Id-1 expression was elevated in OS tissues than adjacent normal bone tissues. More importantly, we demonstrated that overexpression of Id-1 is significantly correlated with tumor progression and poor survival in OS patients. Furthermore, increased expression of Id-1 was observed in OS cell lines and ectopic expression of Id-1 significantly enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas knockdown of Id-1 suppressed OS cells growth. Moreover, our experimental data revealed that Id-1 promotes cell proliferation by facilitating cell cycle progression and inhibits cell apoptosis. Mechanistically, the effects of Id-1 in OS cells is at least partly through activation of PI3K/Akt signaling pathway. Therefore, we identified a tumorigenic role of Id-1 in OS and suggested a potential therapeutic target for OS patients. PMID:26797271

  11. Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK–NF-κB signaling pathway

    SciTech Connect

    Che, Qi; Liu, Bin-Ya; Wang, Fang-Yuan; He, Yin-Yan; Lu, Wen; Liao, Yun; Gu, Wei; Wan, Xiao-Ping

    2014-03-28

    Highlights: • IL-6 could promote endometrial cancer cells proliferation. • IL-6 promotes its own production through an autocrine feedback loop. • ERK and NF-κB pathway inhibitors inhibit IL-6 production and tumor growth. • IL-6 secretion relies on the activation of ERK–NF-κB pathway axis. • An orthotopic nude endometrial carcinoma model confirms the effect of IL-6. - Abstract: Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In this study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK–NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma.

  12. Involvement of Wnt/β-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma

    PubMed Central

    Yuan, Jiahui; Yan, Congcong; Hu, Shaoping; Tong, Yinping; Mao, Yubin; Hu, Tianhui; Zhang, Bing; Song, Gang

    2015-01-01

    Mesenchymal stem cells (MSCs) are multi-potent progenitor cells with ability to differentiate into multiple lineages, including bone, cartilage, fat, and muscles. Recent research indicates that MSCs can be efficiently recruited to tumor sites, modulating tumor growth and metastasis. However, the underlying molecular mechanisms are not fully understood. Here, we first demonstrated that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), when mixed with human cholangiocarcinoma cell lines QBC939 in a xenograft tumor model, significantly increased the cancer cells proliferation and metastatic potency. MSCs and their conditioned media (MSC-CM) could improve the drug resistance of tumor when the compound K (CK) as an anti-cancer drug, a major intestinal bacterial metabolite of panaxoside, was administered to xenograft tumor mice. Furthermore, MSCs greatly increased the colony formation and invasion of cholangiocarcinoma cells QBC939 and Mz-ChA-1. Immunochemistry studies of cholangiocarcinoma tissue chips and transplantation tumor from nude mice showed that the expression of β-catenin was important for cholangiocarcinoma development. We further demonstrated that MSCs and MSCs-CM could promote proliferation and migration of cholangiocarcinoma cells through targeting the Wnt/β-catenin signaling pathway. hUC-MSCs or MSCs-CM stimulated Wnt activity by promoting the nuclear translocation of β-catenin, and up-regulated Wnt target genes MMPs family, cyclin D1 and c-Myc. Together, our studies highlight a critical role for MSCs on cancer metastasis and indicate MSCs promote metastatic growth and chemoresistance of cholangiocarcinoma cells via activation of Wnt/β-catenin signaling. PMID:26474277

  13. Taurolithocholic acid promotes intrahepatic cholangiocarcinoma cell growth via muscarinic acetylcholine receptor and EGFR/ERK1/2 signaling pathway

    PubMed Central

    AMONYINGCHAROEN, SUMET; SURIYO, TAWIT; THIANTANAWAT, APINYA; WATCHARASIT, PIYAJIT; SATAYAVIVAD, JUTAMAAD

    2015-01-01

    Cholangiocarcinoma (CCA) is a malignant cancer of the biliary tract and its occurrence is associated with chronic cholestasis which causes an elevation of bile acids in the liver and bile duct. The present study aimed to investigate the role and mechanistic effect of bile acids on the CCA cell growth. Intrahepatic CCA cell lines, RMCCA-1 and HuCCA-1, were treated with bile acids and their metabolites to determine the growth promoting effect. Cell viability, cell cycle analysis, EdU incorporation assays were conducted. Intracellular signaling proteins were detected by western immunoblotting. Among eleven forms of bile acids and their metabolites, only taurolithocholic acid (TLCA) concentration dependently (1–40 μM) increased the cell viability of RMCCA-1, but not HuCCA-1 cells. The cell cycle analysis showed induction of cells in the S phase and the EdU incorporation assay revealed induction of DNA synthesis in the TLCA-treated RMCCA-1 cells. Moreover, TLCA increased the phosphorylation of EGFR, ERK 1/2 and also increased the expression of cyclin D1 in RMCCA-1 cells. Furthermore, TLCA-induced RMCCA-1 cell growth could be inhibited by atropine, a non-selective muscarinic acetylcholine receptor (mAChR) antagonist, AG 1478, a specific EGFR inhibitor, or U 0126, a specific MEK 1/2 inhibitor. These results suggest that TLCA induces CCA cell growth via mAChR and EGFR/EKR1/2 signaling pathway. Moreover, the functional presence of cholinergic system plays a certain role in TLCA-induced CCA cell growth. PMID:25815516

  14. Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK-NF-κB signaling pathway.

    PubMed

    Che, Qi; Liu, Bin-Ya; Wang, Fang-Yuan; He, Yin-Yan; Lu, Wen; Liao, Yun; Gu, Wei; Wan, Xiao-Ping

    2014-03-28

    Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In this study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK-NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma. PMID:24582558

  15. PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma

    SciTech Connect

    Zhuo, Baobiao; Li, Yuan; Li, Zhengwei; Qin, Haihui; Sun, Qingzeng; Zhang, Fengfei; Shen, Yang; Shi, Yingchun; Wang, Rong

    2015-08-21

    Accumulating evidence has shown that PI3K/Akt pathway is frequently hyperactivated in osteosarcoma (OS) and contributes to tumor initiation and progression. Altered phenotype of glucose metabolism is a key hallmark of cancer cells including OS. However, the relationship between PI3K/Akt pathway and glucose metabolism in OS remains largely unexplored. In this study, we showed that elevated Hexokinase-2 (HK2) expression, which catalyzes the first essential step of glucose metabolism by conversion of glucose into glucose-6-phosphate, was induced by activated PI3K/Akt signaling. Immunohistochemical analysis showed that HK2 was overexpressed in 83.3% (25/30) specimens detected and was closely correlated with Ki67, a cell proliferation index. Silencing of endogenous HK2 resulted in decreased aerobic glycolysis as demonstrated by reduced glucose consumption and lactate production. Inhibition of PI3K/Akt signaling also suppressed aerobic glycolysis and this effect can be reversed by reintroduction of HK2. Furthermore, knockdown of HK2 led to increased cell apoptosis and reduced ability of colony formation; meanwhile, these effects were blocked by 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor through its actions on hexokinase, indicating that HK2 functions in cell apoptosis and growth were mediated by altered aerobic glycolysis. Taken together, our study reveals a novel relationship between PI3K/Akt signaling and aerobic glycolysis and indicates that PI3K/Akt/HK2 might be potential therapeutic approaches for OS. - Highlights: • PI3K/Akt signaling contributes to elevated expression of HK2 in osteosarcoma. • HK2 inhibits cell apoptosis and promotes tumor growth through enhanced Warburg effect. • Inhibition of glycolysis blocks the oncogenic activity of HK2.

  16. Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway

    PubMed Central

    Chou, Chih-Hsing; Huang, Miao-Juei; Chen, Chi-Hau; Shyu, Ming-Kwang; Huang, John; Hung, Ji-Shiang; Huang, Chiun-Sheng; Huang, Min-Chuan

    2015-01-01

    Aberrant glycosylation is frequently observed in cancers. Core 1 β1,3-galactosyltransferase (C1GALT1) is an exclusive enzyme in humans that catalyzes the biosynthesis of core 1 O-glycan structure, Gal-GalNAc-O-Ser/Thr, whose expression is commonly up-regulated during tumorigenesis. Little is known about the function of C1GALT1 in breast cancer. This study aims to determine the correlation between C1GALT1 expression and breast cancer clinicopathological features and roles of C1GALT1 in breast cancer malignant phenotypes. Public databases and our data showed that C1GALT1 mRNA and C1GALT1 protein are frequently up-regulated in breast cancer; and increased C1GALT1 expression correlates with higher histological grade and advanced tumor stage. Overexpression of C1GALT1 enhanced breast cancer cell growth, migration, and invasion in vitro as well as tumor growth in vivo. Conversely, C1GALT1 knockdown suppressed these malignant phenotypes. Furthermore, C1GALT1 modulates O-glycan structures on Mucin (MUC) 1 and promotes MUC1-C/β-catenin signaling in breast cancer cells. These findings suggest that C1GALT1 enhances breast cancer malignant progression through promoting MUC1-C/β-catenin signaling pathway. Unveiling the function of C1GALT1 in breast cancer opens new insights to the roles of C1GALT1 and O-glycosylation in tumorigenesis and renders the potential of C1GALT1 as a target of novel therapeutic agent development. PMID:25762620

  17. PSMB4 promotes multiple myeloma cell growth by activating NF-κB-miR-21 signaling

    SciTech Connect

    Zheng, Peihao; Guo, Honggang; Li, Guangchao; Han, Siqi; Luo, Fei; Liu, Yi

    2015-03-06

    Proteasomal subunit PSMB4, was recently identified as potential cancer driver genes in several tumors. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we investigated the expression and roles of PSMB4 in multiple myeloma (MM). We found a significant up-regulation of PSMB4 in MM plasma and cell lines. Ectopic overexpression of PSMB4 promoted cell growth and colony forming ability of MM cells, whereas inhibition of PSMB4 led to a decrease of such events. Furthermore, our results demonstrated the up-regulation of miR-21 and a positive correlation between the levels of miR-21 and PSMB4 in MM. Re-expression of miR-21 markedly rescued PSMB4 knockdown-mediated suppression of cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of miR-21, PSMB4 knockdown or NF-κB inhibition suppressed miR-21 expression in MM cells. Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-κB-miR-21 signaling, which may represent promising targets for novel specific therapies. - Highlights: • First reported upregulation of PSMB4 in MM plasma and cell lines. • PSMB4 promoted MM cell growth and colony forming ability. • Further found miR-21 was up-regulated by PSMB4 in MM plasma and cell lines. • PSMB4-induced miR-21 expression was modulated by NF-κB. • PSMB4-NF-κB-miR-21 axis may be potential therapeutic targets of MM.

  18. A Complex Molecular Interplay of Auxin and Ethylene Signaling Pathways Is Involved in Arabidopsis Growth Promotion by Burkholderia phytofirmans PsJN.

    PubMed

    Poupin, María J; Greve, Macarena; Carmona, Vicente; Pinedo, Ignacio

    2016-01-01

    Modulation of phytohormones homeostasis is one of the proposed mechanisms to explain plant growth promotion induced by beneficial rhizobacteria (PGPR). However, there is still limited knowledge about the molecular signals and pathways underlying these beneficial interactions. Even less is known concerning the interplay between phytohormones in plants inoculated with PGPR. Auxin and ethylene are crucial hormones in the control of plant growth and development, and recent studies report an important and complex crosstalk between them in the regulation of different plant developmental processes. The objective of this work was to study the role of both hormones in the growth promotion of Arabidopsis thaliana plants induced by the well-known PGPR Burkholderia phytofirmans PsJN. For this, the spatiotemporal expression patterns of several genes related to auxin biosynthesis, perception and response and ethylene biosynthesis were studied, finding that most of these genes showed specific transcriptional regulations after inoculation in roots and shoots. PsJN-growth promotion was not observed in Arabidopsis mutants with an impaired ethylene (ein2-1) or auxin (axr1-5) signaling. Even, PsJN did not promote growth in an ethylene overproducer (eto2), indicating that a fine regulation of both hormones signaling and homeostasis is necessary to induce growth of the aerial and root tissues. Auxin polar transport is also involved in growth promotion, since PsJN did not promote primary root growth in the pin2 mutant or under chemical inhibition of transport in wild type plants. Finally, a key role for ethylene biosynthesis was found in the PsJN-mediated increase in root hair number. These results not only give new insights of PGPR regulation of plant growth but also are also useful to understand key aspects of Arabidopsis growth control. PMID:27148317

  19. A Complex Molecular Interplay of Auxin and Ethylene Signaling Pathways Is Involved in Arabidopsis Growth Promotion by Burkholderia phytofirmans PsJN

    PubMed Central

    Poupin, María J.; Greve, Macarena; Carmona, Vicente; Pinedo, Ignacio

    2016-01-01

    Modulation of phytohormones homeostasis is one of the proposed mechanisms to explain plant growth promotion induced by beneficial rhizobacteria (PGPR). However, there is still limited knowledge about the molecular signals and pathways underlying these beneficial interactions. Even less is known concerning the interplay between phytohormones in plants inoculated with PGPR. Auxin and ethylene are crucial hormones in the control of plant growth and development, and recent studies report an important and complex crosstalk between them in the regulation of different plant developmental processes. The objective of this work was to study the role of both hormones in the growth promotion of Arabidopsis thaliana plants induced by the well-known PGPR Burkholderia phytofirmans PsJN. For this, the spatiotemporal expression patterns of several genes related to auxin biosynthesis, perception and response and ethylene biosynthesis were studied, finding that most of these genes showed specific transcriptional regulations after inoculation in roots and shoots. PsJN-growth promotion was not observed in Arabidopsis mutants with an impaired ethylene (ein2-1) or auxin (axr1–5) signaling. Even, PsJN did not promote growth in an ethylene overproducer (eto2), indicating that a fine regulation of both hormones signaling and homeostasis is necessary to induce growth of the aerial and root tissues. Auxin polar transport is also involved in growth promotion, since PsJN did not promote primary root growth in the pin2 mutant or under chemical inhibition of transport in wild type plants. Finally, a key role for ethylene biosynthesis was found in the PsJN-mediated increase in root hair number. These results not only give new insights of PGPR regulation of plant growth but also are also useful to understand key aspects of Arabidopsis growth control. PMID:27148317

  20. Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling.

    PubMed

    Ramachandra, Rashmi; Namburi, Ramesh B; Ortega-Martinez, Olga; Shi, Xiaofeng; Zaia, Joseph; Dupont, Sam T; Thorndyke, Michael C; Lindahl, Ulf; Spillmann, Dorothe

    2014-02-01

    Glycosaminoglycans (GAGs) isolated from brittlestars, Echinodermata class Ophiuroidea, were characterized, as part of attempts to understand the evolutionary development of these polysaccharides. A population of chondroitin sulfate/dermatan sulfate (CS/DS) chains with a high overall degree of sulfation and hexuronate epimerization was the major GAG found, whereas heparan sulfate (HS) was below detection level. Enzymatic digestion with different chondroitin lyases revealed exceptionally high proportions of di- and trisulfated CS/DS disaccharides. The latter unit appears much more abundant in one of four individual species of brittlestars, Amphiura filiformis, than reported earlier in other marine invertebrates. The brittlestar CS/DS was further shown to bind to growth factors such as fibroblast growth factor 2 and to promote FGF-stimulated cell signaling in GAG-deficient cell lines in a manner similar to that of heparin. These findings point to a potential biological role for the highly sulfated invertebrate GAGs, similar to those ascribed to HS in vertebrates. PMID:24253764

  1. The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway.

    PubMed

    Su, Ke; Wang, Chun-Fang; Zhang, Ying; Cai, Yu-Jie; Zhang, Yan-Yan; Zhao, Qian

    2016-08-01

    Cervical cancer has been the fourth most common cancer killing many women across the world. Carnosic acid (CA), as a phenolic diterpene, has been suggested to against cancer, exerting protective effects associated with inflammatory cytokines. It is aimed to demonstrate the therapeutic role of carnosic acid against cervical cancer and indicate its underlying molecular mechanisms. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was performed to assess the possible anti-proliferative effects of carnosic acid. And also, colony formation was used to further estimate carnosic acid's ability in suppressing cervical cancer cells proliferation. Flow cytometry assays were performed here to indicate the alterations of cervical cancer cells cycle and the development of apoptosis. Western blot assays and RT-PCR were also applied to clarify the apoptosis-associated signaling pathways affected by reactive oxygen species (ROS) generation. And immunofluorescence was used to detect ROS-positive cells. In vivo experiments, CaSki xenograft model samples of nude mice were involved to further elucidate the effects of carnosic acid. In our results, we found that carnosic acid exerted anti-tumor ability in vitro supported by up-regulation of apoptosis and ROS production in cervical cancer cells. Also, acceleration of ROS led to the phospharylation of (c-Jun N-terminal kinase (JNK) and its-related signals, as well as activation of Endoplasmic Reticulum (ER) stress, promoting the progression of apoptosis via stimulating Caspase3 expression. The development and growth of xenograft tumors in nude mice were found to be inhibited by the administration of carnosic acid for five weeks. And the suppressed role of carnosic acid in proliferation of cervical cancer cells and apoptosis of nude mice with tumor tissues were observed in our study. Taken together, our data indicated that carnosic acid resulted in apoptosis both in vitro and vivo experiments via promoting ROS and

  2. Insulin-like growth factor-1 (IGF-1) promotes myoblast proliferation and skeletal muscle growth of embryonic chickens via the PI3K/Akt signalling pathway.

    PubMed

    Yu, Minli; Wang, Huan; Xu, Yali; Yu, Debing; Li, Dongfeng; Liu, Xiuhong; Du, Wenxing

    2015-08-01

    During embryonic development, IGF-1 fulfils crucial roles in skeletal myogenesis. However, the involvement of IGF-1-induced myoblast proliferation in muscle growth is still unclear. In the present study, we have characterised the role of IGF-1 in myoblast proliferation both in vitro and in vivo and have revealed novel details of how exogenous IGF-1 influences myogenic genes in chicken embryos. The results show that IGF-1 significantly induces the proliferation of cultured myoblasts in a dose-dependent manner. Additionally, the IGF-1 treatment significantly promoted myoblasts entering a new cell cycle and increasing the mRNA expression levels of cell cycle-dependent genes. However, these effects were inhibited by the PI3K inhibitor LY294002 and the Akt inhibitor KP372-1. These data indicated that the pro-proliferative effect of IGF-1 was mediated in response to the PI3K/Akt signalling pathway. Moreover, we also showed that exogenous IGF-1 stimulated myoblast proliferation in vivo. IGF-1 administration obviously promoted the incorporation of BrdU and remarkably increased the number of PAX7-positive cells in the skeletal muscle of chicken embryos. Administration of IGF-1 also significantly induced the upregulation of myogenic factors gene, the enhancement of c-Myc and the inhibition of myostatin (Mstn) expression. These findings demonstrate that IGF-1 has strong activity as a promoter of myoblast expansion and muscle fiber formation during early myogenesis. Therefore, this study offers insight into the mechanisms responsible for IGF-1-mediated stimulation of embryonic skeletal muscle development, which could have important implications for the improvement of chicken meat production. PMID:25808997

  3. Growth hormone signaling pathways.

    PubMed

    Carter-Su, Christin; Schwartz, Jessica; Argetsinger, Lawrence S

    2016-06-01

    Over 20years ago, our laboratory showed that growth hormone (GH) signals through the GH receptor-associated tyrosine kinase JAK2. We showed that GH binding to its membrane-bound receptor enhances binding of JAK2 to the GHR, activates JAK2, and stimulates tyrosyl phosphorylation of both JAK2 and GHR. The activated JAK2/GHR complex recruits a variety of signaling proteins, thereby initiating multiple signaling pathways and cellular responses. These proteins and pathways include: 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin-like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein α, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton. Our recent work has focused on the function of SH2B1. We have shown that SH2B1β is recruited to and phosphorylated by JAK2 in response to GH. SH2B1 localizes to the plasma membrane, cytoplasm and focal adhesions; it also cycles through the nucleus. SH2B1 regulates the actin cytoskeleton and promotes GH-dependent motility of RAW264.7 macrophages. Mutations in SH2B1 have been found in humans exhibiting severe early-onset childhood obesity and insulin resistance. These mutations impair SH2B1 enhancement of GH-induced macrophage motility. As SH2B1 is expressed ubiquitously and is also recruited to a variety of receptor tyrosine kinases, our results raise the possibility that effects of SH2B1 on the actin cytoskeleton in various cell types, including neurons, may play a role in regulating body weight. PMID:26421979

  4. The Pollen Receptor Kinase LePRK2 Mediates Growth-Promoting Signals and Positively Regulates Pollen Germination and Tube Growth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In flowering plants, the process of pollen germination and tube growth is required for successful fertilization. A pollen receptor kinase from tomato, LePRK2, has been implicated in signaling during pollen germination and tube growth as well as in mediating pollen (tube)-pistil communication. Here w...

  5. Loss of large tumor suppressor 1 promotes growth and metastasis of gastric cancer cells through upregulation of the YAP signaling

    PubMed Central

    Chu, Shao-Jun; Zhu, Jin-Shui; Zhang, Rui; Lu, Wen-Wen; Xia, Li-Qiong; Lu, Yun-Min; Da, Wei; Sun, Qun

    2016-01-01

    Accumulating evidence shows that large tumor suppressor 1 (LATS1) as a novel resident governor of cellular homeostasis is implicated in multiple tumorigenic properties including cell growth, apoptosis and metastasis. However, the contribution of LATS1 to gastric carcinoma (GC) remains unclear. The correlation of LATS1 expression with clinicopathologic characteristics, GC prognosis and recurrence was analyzed by immunohistochemistry, Univariate and Kaplan-Meier analysis. Functional experiments were performed to investigate biological behaviors of GC cells and underlying molecular mechanisms. Tumor growth and metastasis was assessed in vivo using orthotopic implantation GC models in severe combined immune deficiency (SCID) mice. Consequently, decreased LATS1 expression was significantly associated with the lymph node metastasis, poor prognosis and recurrence. Ectopic expression of LATS1 decreased GC cell proliferation and invasion in vitro and inhibited tumor growth and liver metastasis in vivo, but depletion of LATS1 expression restored the invasive phenotype. Further observation indicated that YAP pathway was required for LATS1-induced inhibition of cell growth and invasion, and LATS1 restrained nuclear transfer of YAP, downregulated YAP, PCNA, CTGF, MMP-2, MMP-9, Bcl-2 and CyclinD1 expression and upregulated p-YAP and Bax expression. Our findings suggest that LATS1 is a potential candidate tumor suppressor and inhibits the growth and metastasis of GC cells via downregulation of the YAP signaling. PMID:26921249

  6. Nodal Promotes Glioblastoma Cell Growth

    PubMed Central

    De Silva, Tanya; Ye, Gang; Liang, Yao-Yun; Fu, Guodong; Xu, Guoxiong; Peng, Chun

    2012-01-01

    Nodal is a member of the transforming growth factor-β (TGF-β) superfamily that plays critical roles during embryogenesis. Recent studies in ovarian, breast, prostate, and skin cancer cells suggest that Nodal also regulates cell proliferation, apoptosis, and invasion in cancer cells. However, it appears to exert both tumor-suppressing and tumor-promoting effects, depending on the cell type. To further understand the role of Nodal in tumorigenesis, we examined the effect of Nodal in glioblastoma cell growth and spheroid formation using U87 cell line. Treatment of U87 with recombinant Nodal significantly increased U87 cell growth. In U87 cells stably transfected with the plasmid encoding Nodal, Smad2 phosphorylation was strongly induced and cell growth was significantly enhanced. Overexpression of Nodal also resulted in tight spheroid formation. On the other hand, the cells stably transfected with Nodal siRNA formed loose spheroids. Nodal is known to signal through activin receptor-like kinase 4 (ALK4) and ALK7 and the Smad2/3 pathway. To determine which receptor and Smad mediate the growth promoting effect of Nodal, we transfected siRNAs targeting ALK4, ALK7, Smad2, or Smad3 into Nodal-overexpressing cells and observed that cell growth was significantly inhibited by ALK4, ALK7, and Smad3 siRNAs. Taken together, these findings suggest that Nodal may have tumor-promoting effects on glioblastoma cells and these effects are mediated by ALK4, ALK7, and Smad3. PMID:22645523

  7. FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.

    PubMed

    Mak, Victor C Y; Wong, Oscar G W; Siu, Michelle K Y; Wong, Esther S Y; Ng, Wai-Yan; Wong, Richard W C; Chan, Ka-Kui; Ngan, Hextan Y S; Cheung, Annie N Y

    2015-07-01

    Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts. PMID:26093985

  8. Chlorpyrifos promotes colorectal adenocarcinoma H508 cell growth through the activation of EGFR/ERK1/2 signaling pathway but not cholinergic pathway.

    PubMed

    Suriyo, Tawit; Tachachartvanich, Phum; Visitnonthachai, Daranee; Watcharasit, Piyajit; Satayavivad, Jutamaad

    2015-12-01

    Aside from the effects on neuronal cholinergic system, epidemiological studies suggest an association between chlorpyrifos (CPF) exposure and cancer risk. This in vitro study examined the effects of CPF and its toxic metabolite, chlorpyrifos oxon (CPF-O), on the growth of human colorectal adenocarcinoma H508, colorectal adenocarcinoma HT-29, normal colon epithelial CCD841, liver hepatocellular carcinoma HepG2, and normal liver hepatocyte THLE-3 cells. The results showed that CPF (5-100 μM) concentration-dependently increased viability of H508 and CCD841 cells in serum-free conditions. This increasing trend was not found in HT-29, HepG2 and THLE-3 cells. In contrast, CPF-O (50-100 μM) reduced the viability of all cell lines. Cell cycle analysis showed the induction of cells in the S phase, and EdU incorporation assay revealed the induction of DNA synthesis in CPF-treated H508 cells indicating that CPF promotes cell cycle progression. Despite the observation of acetylcholinesterase activity inhibition and reactive oxygen species (ROS) generation, atropine (a non-selective muscarinic acetylcholine receptor antagonist) and N-acetylcysteine (a potent antioxidant) failed to inhibit the growth-promoting effect of CPF. CPF increased the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream effector, extracellular signal regulated kinase (ERK1/2), in H508 cells. AG-1478 (a specific EGFR tyrosine kinase inhibitor) and U0126 (a specific MEK inhibitor) completely mitigated the growth promoting effect of CPF. Altogether, these results suggest that EGFR/ERK1/2 signaling pathway but not cholinergic pathway involves in CPF-induced colorectal adenocarcinoma H508 cell growth. PMID:26514924

  9. Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma.

    PubMed

    Wu, Xiao; Liu, Bao-Jun; Ji, Shumeng; Wu, Jing-Feng; Xu, Chang-Qing; Du, Yi-Jie; You, Xiao-Fang; Li, Bei; Le, Jing-Jing; Xu, Hai-Lin; Duan, Xiao-Hong; Dong, Jing-Cheng

    2015-07-01

    Numerous epidemiological and experimental animal studies have indicated that chronic psychological stress may promote tumor development. However, the underlying molecular mechanisms by which chronic stress promotes tumorigenesis remain to be fully elucidated and animal models have not yet been well established. In the present study, an established mouse model of repeated social defeat stress (RSDS), was generated and used to investigate the effect of stress on tumor growth and metastasis. C57BL/6 mice were exposed to RSDS for 10 days, followed by subcutaneousl inoculation with Lewis lung carcinoma cells for seven days. The tumor weight and volume as well as the number of the lung metastatic nodules were then determined. Vascular endothelial growth factor (VEGF) serum levels were measured using ELISAs. In addition, expression levels of VEGF receptor (VEGFR) and L1 cell adhesion molecule (L1CAM) messenger (m)RNA were confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, protein expression levels of phosphorlyated extracellular signal-regulated kinase (pERK), matrix metalloproteinase (MMP)-2 and MMP-9 were examined using western blot analysis. The results showed that RSDS significantly increased the weight and the volume of the primary tumor as well as the number of the lung metastatic nodules. Serum VEGF levels were significantly higher in the tumor-stress group compared with those of the unstressed tumor mice. In addition, tumors in stressed animals demonstrated markedly enhanced expression of VEGFR-2 and L1CAM mRNA as well as pERK, MMP-2 and MMP-9 protein expression. In conclusion, these results suggested that RSDS contributed to lung cancer progression, angiogenesis and metastasis, which was partially associated with increased VEGF secretion and therefore the activation of the ERK signaling pathway, resulting in the induction of MMP-2 and MMP-9 protein expression. PMID:25824133

  10. Lysine-specific demethylase 1 mediates epidermal growth factor signaling to promote cell migration in ovarian cancer cells.

    PubMed

    Shao, Genbao; Wang, Jie; Li, Yuanxia; Liu, Xiuwen; Xie, Xiaodong; Wan, Xiaolei; Yan, Meina; Jin, Jie; Lin, Qiong; Zhu, Haitao; Zhang, Liuping; Gong, Aihua; Shao, Qixiang; Wu, Chaoyang

    2015-01-01

    Epigenetic abnormalities play a vital role in the progression of ovarian cancer. Lysine-specific demethylase 1 (LSD1/KDM1A) acts as an epigenetic regulator and is overexpressed in ovarian tumors. However, the upstream regulator of LSD1 expression in this cancer remains elusive. Here, we show that epidermal growth factor (EGF) signaling upregulates LSD1 protein levels in SKOV3 and HO8910 ovarian cancer cells overexpressing both LSD1 and the EGF receptor. This effect is correlated with a decrease in the dimethylation of H3K4, a major substrate of LSD1, in an LSD1-dependent manner. We also show that inhibition of PI3K/AKT, but not MEK, abolishes the EGF-induced upregulation of LSD1 and cell migration, indicating that the PI3K/PDK1/AKT pathway mediates the EGF-induced expression of LSD1 and cell migration. Significantly, LSD1 knockdown or inhibition of LSD1 activity impairs both intrinsic and EGF-induced cell migration in SKOV3 and HO8910 cells. These results highlight a novel mechanism regulating LSD1 expression and identify LSD1 as a promising therapeutic target for treating metastatic ovarian cancer driven by EGF signaling. PMID:26489763

  11. DNA signals at isoform promoters

    PubMed Central

    Dai, Zhiming; Xiong, Yuanyan; Dai, Xianhua

    2016-01-01

    Transcriptional heterogeneity is extensive in the genome, and most genes express variable transcript isoforms. However, whether variable transcript isoforms of one gene are regulated by common promoter elements remain to be elucidated. Here, we investigated whether isoform promoters of one gene have separated DNA signals for transcription and translation initiation. We found that TATA box and nucleosome-disfavored DNA sequences are prevalent in distinct transcript isoform promoters of one gene. These DNA signals are conserved among species. Transcript isoform has a RNA-determined unstructured region around its start site. We found that these DNA/RNA features facilitate isoform transcription and translation. These results suggest a DNA-encoded mechanism by which transcript isoform is generated. PMID:27353836

  12. DNA signals at isoform promoters.

    PubMed

    Dai, Zhiming; Xiong, Yuanyan; Dai, Xianhua

    2016-01-01

    Transcriptional heterogeneity is extensive in the genome, and most genes express variable transcript isoforms. However, whether variable transcript isoforms of one gene are regulated by common promoter elements remain to be elucidated. Here, we investigated whether isoform promoters of one gene have separated DNA signals for transcription and translation initiation. We found that TATA box and nucleosome-disfavored DNA sequences are prevalent in distinct transcript isoform promoters of one gene. These DNA signals are conserved among species. Transcript isoform has a RNA-determined unstructured region around its start site. We found that these DNA/RNA features facilitate isoform transcription and translation. These results suggest a DNA-encoded mechanism by which transcript isoform is generated. PMID:27353836

  13. Bacterial volatiles promote growth in Arabidopsis

    PubMed Central

    Ryu, Choong-Min; Farag, Mohamed A.; Hu, Chia-Hui; Reddy, Munagala S.; Wei, Han-Xun; Paré, Paul W.; Kloepper, Joseph W.

    2003-01-01

    Several chemical changes in soil are associated with plant growth-promoting rhizobacteria (PGPR). Some bacterial strains directly regulate plant physiology by mimicking synthesis of plant hormones, whereas others increase mineral and nitrogen availability in the soil as a way to augment growth. Identification of bacterial chemical messengers that trigger growth promotion has been limited in part by the understanding of how plants respond to external stimuli. With an increasing appreciation of how volatile organic compounds signal plants and serve in plant defense, investigations into the role of volatile components in plant–bacterial systems now can follow. Here, we present chemical and plant-growth data showing that some PGPR release a blend of volatile components that promote growth of Arabidopsis thaliana. In particular, the volatile components 2,3-butanediol and acetoin were released exclusively from two bacterial strains that trigger the greatest level of growth promotion. Furthermore, pharmacological applications of 2,3-butanediol enhanced plant growth whereas bacterial mutants blocked in 2,3-butanediol and acetoin synthesis were devoid in this growth-promotion capacity. The demonstration that PGPR strains release different volatile blends and that plant growth is stimulated by differences in these volatile blends establishes an additional function for volatile organic compounds as signaling molecules mediating plant–microbe interactions. PMID:12684534

  14. Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A

    PubMed Central

    Yang, Yang; Zhang, Mei-Yin; Rao, Hui-Lan; Wang, Hui-Yun; Zheng, X.F. Steven

    2015-01-01

    mTORC1 is a master regulator of cell growth and proliferation, and an established anticancer drug target. Aberrant mTORC1 signaling is common in hepatocellular carcinoma (HCC), but the underlying mechanism remains elusive. Rab1A is a newly identified mTORC1 activator that mediates an alternative amino acid (AA) signaling branch to Rag GTPases. Because liver is a physiological hub for nutrient sensing and metabolic homeostasis, we investigated the possible role of Rab1A in HCC. We found that Rab1A is frequently overexpressed in HCC, which enhances hyperactive AA-mTORC1 signaling, promoting malignant growth and metastasis of HCC in vitro and in vivo. Moreover, aberrant Rab1A expression is closely associated with poor prognosis. Strikingly, aberrant Rab1A overexpression leads to increased rapamycin sensitivity, indicating that inappropriate activation of AA signaling is a cancer-driving event in HCC. Our findings further suggest that Rab1A is a valuable biomarker for prognosis and personalized mTORC1-targeted therapy in liver cancer. PMID:26308575

  15. A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: Activation of proteinase-activated receptor 1 and epidermal growth factor receptor

    SciTech Connect

    Gao, Lin; Chao, Lee; Chao, Julie

    2010-02-01

    Biological functions of tissue kallikrein (TK, KLK1) are mainly mediated by kinin generation and subsequent kinin B2 receptor activation. In this study, we investigated the potential role of TK and its signaling pathways in cultured human keratinocyte migration and in a rat skin wound healing model. Herein, we show that TK promoted cell migration and proliferation in a concentration- and time-dependent manner. Inactive TK or kinin had no significant effect on cell migration. Interestingly, cell migration induced by active TK was not blocked by icatibant or L-NAME, indicating an event independent of kinin B2 receptor and nitric oxide formation. TK's stimulatory effect on cell migration was inhibited by small interfering RNA for proteinase-activated receptor 1 (PAR{sub 1}), and by PAR{sub 1} inhibitor. TK-induced migration was associated with increased phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), which was blocked by inhibition of protein kinase C (PKC), Src, EGFR and ERK. TK-induced cell migration and EGFR phosphorylation were blocked by metalloproteinase (MMP) inhibitor, heparin, and antibodies against EGFR external domain, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR). Local application of TK promoted skin wound healing in rats, whereas icatibant and EGFR inhibitor blocked TK's effect. Skin wound healing was further delayed by aprotinin and neutralizing TK antibody. This study demonstrates a novel role of TK in skin wound healing and uncovers new signaling pathways mediated by TK in promoting keratinocyte migration through activation of the PAR{sub 1}-PKC-Src-MMP pathway and HB-EGF/AR shedding-dependent EGFR transactivation.

  16. Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling.

    PubMed

    Diniz, Luan Pereira; Tortelli, Vanessa; Garcia, Matheus Nunes; Araújo, Ana Paula Bérgamo; Melo, Helen M; Silva, Gisele S Seixas da; Felice, Fernanda G De; Alves-Leon, Soniza Vieira; Souza, Jorge Marcondes de; Romão, Luciana Ferreira; Castro, Newton Gonçalves; Gomes, Flávia Carvalho Alcantara

    2014-12-01

    The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-β1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-β pathway. TGF-β1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-β1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-β1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-β1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission. PMID:25042347

  17. Growth Hormone Promotes Lymphangiogenesis

    PubMed Central

    Banziger-Tobler, Nadja Erika; Halin, Cornelia; Kajiya, Kentaro; Detmar, Michael

    2008-01-01

    The lymphatic system plays an important role in inflammation and cancer progression, although the molecular mechanisms involved are poorly understood. As determined using comparative transcriptional profiling studies of cultured lymphatic endothelial cells versus blood vascular endothelial cells, growth hormone receptor was expressed at much higher levels in lymphatic endothelial cells than in blood vascular endothelial cells. These findings were confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blot analyses. Growth hormone induced in vitro proliferation, sprouting, tube formation, and migration of lymphatic endothelial cells, and the mitogenic effect was independent of vascular endothelial growth factor receptor-2 or -3 activation. Growth hormone also inhibited serum starvation-induced lymphatic endothelial cell apoptosis. No major alterations of lymphatic vessels were detected in the normal skin of bovine growth hormone-transgenic mice. However, transgenic delivery of growth hormone accelerated lymphatic vessel ingrowth into the granulation tissue of full-thickness skin wounds, and intradermal delivery of growth hormone resulted in enlargement and enhanced proliferation of cutaneous lymphatic vessels in wild-type mice. These results identify growth hormone as a novel lymphangiogenic factor. PMID:18583315

  18. Plant growth promoting rhizobacterium

    SciTech Connect

    Doktycz, Mitchel John; Pelletier, Dale A.; Schadt, Christopher Warren; Tuskan, Gerald A.; Weston, David

    2015-08-11

    The present invention is directed to the Pseudomonas fluorescens strain GM30 deposited under ATCC Accession No. PTA-13340, compositions containing the GM30 strain, and methods of using the GM30 strain to enhance plant growth and/or enhance plant resistance to pathogens.

  19. Calcium Input Potentiates the Transforming Growth Factor (TGF)-β1-dependent Signaling to Promote the Export of Inorganic Pyrophosphate by Articular Chondrocyte*

    PubMed Central

    Cailotto, Frederic; Reboul, Pascal; Sebillaud, Sylvie; Netter, Patrick; Jouzeau, Jean-Yves; Bianchi, Arnaud

    2011-01-01

    Transforming growth factor (TGF)-β1 stimulates extracellular PPi (ePPi) generation and promotes chondrocalcinosis, which also occurs secondary to hyperparathyroidism-induced hypercalcemia. We previously demonstrated that ANK was up-regulated by TGF-β1 activation of ERK1/2 and Ca2+-dependent protein kinase C (PKCα). Thus, we investigated mechanisms by which calcium could affect ePPi metabolism, especially its main regulating proteins ANK and PC-1 (plasma cell membrane glycoprotein-1). We stimulated articular chondrocytes with TGF-β1 under extracellular (eCa2+) or cytosolic Ca2+ (cCa2+) modulations. We studied ANK, PC-1 expression (quantitative RT-PCR, Western blotting), ePPi levels (radiometric assay), and cCa2+ input (fluorescent probe). Voltage-operated Ca2+-channels (VOC) and signaling pathways involved were investigated with selective inhibitors. Finally, Ank promoter activity was evaluated (gene reporter). TGF-β1 elevated cCa2+ and ePPi levels (by up-regulating Ank and PC-1 mRNA/proteins) in an eCa2+ dose-dependent manner. TGF-β1 effects were suppressed by cCa2+ chelation or L- and T-VOC blockade while being mostly reproduced by ionomycin. In the same experimental conditions, the activation of Ras, the phosphorylation of ERK1/2 and PKCα, and the stimulation of Ank promoter activity were affected similarly. Activation of SP1 (specific protein 1) and ELK-1 (Ets-like protein-1) transcription factors supported the regulatory role of Ca2+. SP1 or ELK-1 overexpression or blockade experiments demonstrated a major contribution of ELK-1, which acted synergistically with SP1 to activate Ank promoter in response to TGF-β1. TGF-β1 promotes input of eCa2+ through opening of L- and T-VOCs, to potentiate ERK1/2 and PKCα signaling cascades, resulting in an enhanced activation of Ank promoter and ePPi production in chondrocyte. PMID:21471198

  20. HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling

    PubMed Central

    Hu, Jiao-Jiao; Song, Wei; Zhang, Shao-Dan; Shen, Xiao-Hui; Qiu, Xue-Mei; Wu, Hua-Zhang; Gong, Pi-Hai; Lu, Sen; Zhao, Zhu-Jiang; He, Ming-Liang; Fan, Hong

    2016-01-01

    It is well accepted that HBx plays the major role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. However, little was known about its role in regulating long noncoding RNAs (lncRNAs), a large group of transcripts regulating a variety of biological processes including carcinogenesis in mammalian cells. Here we report that HBx upregulates UCA1 genes and downregulates p27 genes in hepatic LO2 cells. Further studies show that the upregulated UCA1 promotes cell growth by facilitating G1/S transition through CDK2 in both hepatic and hepatoma cells. Knock down of UCA1 in HBx-expressing hepatic and hepatoma cells resulted in markedly increased apoptotic cells by elevating the cleaved caspase-3 and caspase-8. More importantly, UCA1 is found to be physically associated with enhancer of zeste homolog 2 (EZH2), which suppresses p27Kip1 through histone methylation (H3K27me3) on p27Kip1 promoter. We also show that knockdown of UCA1 in hepatoma cells inhibits tumorigenesis in nude mice. In a clinic study, UCA1 is found to be frequently up-regulated in HBx positive group tissues in comparison with the HBx negative group, and exhibits an inverse correlation between UCA1 and p27Kip1 levels. Our findings demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-UCA1/EZH2-p27Kip1 axis, and a potential target of HCC. PMID:27009634

  1. HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling.

    PubMed

    Hu, Jiao-Jiao; Song, Wei; Zhang, Shao-Dan; Shen, Xiao-Hui; Qiu, Xue-Mei; Wu, Hua-Zhang; Gong, Pi-Hai; Lu, Sen; Zhao, Zhu-Jiang; He, Ming-Liang; Fan, Hong

    2016-01-01

    It is well accepted that HBx plays the major role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. However, little was known about its role in regulating long noncoding RNAs (lncRNAs), a large group of transcripts regulating a variety of biological processes including carcinogenesis in mammalian cells. Here we report that HBx upregulates UCA1 genes and downregulates p27 genes in hepatic LO2 cells. Further studies show that the upregulated UCA1 promotes cell growth by facilitating G1/S transition through CDK2 in both hepatic and hepatoma cells. Knock down of UCA1 in HBx-expressing hepatic and hepatoma cells resulted in markedly increased apoptotic cells by elevating the cleaved caspase-3 and caspase-8. More importantly, UCA1 is found to be physically associated with enhancer of zeste homolog 2 (EZH2), which suppresses p27Kip1 through histone methylation (H3K27me3) on p27Kip1 promoter. We also show that knockdown of UCA1 in hepatoma cells inhibits tumorigenesis in nude mice. In a clinic study, UCA1 is found to be frequently up-regulated in HBx positive group tissues in comparison with the HBx negative group, and exhibits an inverse correlation between UCA1 and p27Kip1 levels. Our findings demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-UCA1/EZH2-p27Kip1 axis, and a potential target of HCC. PMID:27009634

  2. Overexpression of activin-A and -B in malignant mesothelioma – Attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth

    SciTech Connect

    Tamminen, Jenni A.; Yin, Miao; Rönty, Mikko; Sutinen, Eva; Pasternack, Arja; Ritvos, Olli; Myllärniemi, Marjukka; Koli, Katri

    2015-03-01

    Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth. - Highlights: • Activin-A and activin-B are highly expressed in mesothelioma. • Mesothelioma cell migration and invasive growth can be blocked with sActR2B. • Activin induced Smad3 activity is attenuated in invasive mesothelioma cells. • Activins induce ERK activity in mesothelioma cells.

  3. Porous Membrane Substrates Offer Better Niches to Enhance the Wnt Signaling and Promote Human Embryonic Stem Cell Growth and Differentiation

    PubMed Central

    Yao, Huantong; Krisanarungson, Pantrika; Haukas, Andreas; Ye, Kaiming

    2012-01-01

    Human embryonic stem cells (hESCs) require specific niches for adhesion, expansion, and lineage-specific differentiation. In this study, we showed that a membrane substrate offers better tissue niches for hESC attachment, spreading, proliferation, and differentiation. The cell doubling time was shortened from 46.3±5.7 h for hESCs grown on solid substrates to 25.6±2.6 h for those on polyester (PE) membrane substrates with pore size of 0.4 μm. In addition, we observed an increase of approximately five- to ninefold of definitive endoderm marker gene expression in hESCs differentiated on PE or polyethylene terephthalate membrane substrates. Global gene expression analysis revealed upregulated expressions of a number of extracellular matrix and cell adhesion molecules in hESCs grown on membrane substrates. Further, an enhanced nuclear translocation of β-catenin was detected in these cells. These observations suggested the augmentation of Wnt signaling in hESCs grown on membrane substrates. These results also demonstrated that a membrane substrate can offer better physicochemical cues for enhancing in vitro hESC attachment, proliferation, and differentiation. PMID:22429220

  4. Chronic alcohol intake promotes tumor growth in a diethylnitrosamine-induced hepatocarcinogenesis mouse model through increased Wnt/Beta-catenin signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethanol (EtOH) metabolism is involved in both initiating and promoting mechanisms in hepatocellular carcinoma progression in chronic alcoholics. In this study, we developed a mouse model to test the hypothesis that chronic EtOH consumption promotes tumor growth irrespective of EtOH-related initiati...

  5. Signal verification can promote reliable signalling.

    PubMed

    Broom, Mark; Ruxton, Graeme D; Schaefer, H Martin

    2013-11-22

    The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer-resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism. PMID:24068354

  6. Signal verification can promote reliable signalling

    PubMed Central

    Broom, Mark; Ruxton, Graeme D.; Schaefer, H. Martin

    2013-01-01

    The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer–resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism. PMID:24068354

  7. Promoting Intellectual Growth in Adulthood.

    ERIC Educational Resources Information Center

    Kehle, Thomas J.; Bray, Melissa A.; Chafouleas, Sandra M; McLoughlin, Caven S.

    2002-01-01

    Article discusses problems associated with promoting intellectual growth in adulthood. Defines characteristics of intelligent behavior as incorporating individual attainment of Resources, Intimacy, Competence, and Health (RICH). Presents the RICH theory as a way to define and address the goals of intelligent enhancement. (JDM)

  8. Sequential Transphosphorylation of the BRI1/BAK1 Receptor Kinase Pair Regulates Early Events of the Brassinosteriod Signaling Pathway Promoting Plant Growth and Development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brassinosteroids (BRs) regulate multiple aspects of plant growth and development through a signal transduction pathway that is initiated by BR binding to the transmembrane receptor kinase BRI1. Activated BRI1 heterodimerizes with a second receptor kinase, BAK1, leading to enhanced signaling output. ...

  9. Meta-Analysis of Arabidopsis KANADI1 Direct Target Genes Identifies a Basic Growth-Promoting Module Acting Upstream of Hormonal Signaling Pathways.

    PubMed

    Xie, Yakun; Straub, Daniel; Eguen, Tenai; Brandt, Ronny; Stahl, Mark; Martínez-García, Jaime F; Wenkel, Stephan

    2015-10-01

    An intricate network of antagonistically acting transcription factors mediates the formation of a flat leaf lamina of Arabidopsis (Arabidopsis thaliana) plants. In this context, members of the class III homeodomain leucine zipper (HD-ZIPIII) transcription factor family specify the adaxial domain (future upper side) of the leaf, while antagonistically acting KANADI transcription factors determine the abaxial domain (future lower side). Here, we used a messenger RNA sequencing approach to identify genes regulated by KANADI1 (KAN1) and subsequently performed a meta-analysis combining our data sets with published genome-wide data sets. Our analysis revealed that KAN1 acts upstream of several genes encoding auxin biosynthetic enzymes. When exposed to shade, we found three YUCCA genes, YUC2, YUC5, and YUC8, to be transcriptionally up-regulated, which correlates with an increase in the levels of free auxin. When ectopically expressed, KAN1 is able to transcriptionally repress these three YUC genes and thereby block shade-induced auxin biosynthesis. Consequently, KAN1 is able to strongly suppress shade-avoidance responses. Taken together, we hypothesize that HD-ZIPIII/KAN form the basis of a basic growth-promoting module. Hypocotyl extension in the shade and outgrowth of new leaves both involve auxin synthesis and signaling, which are under the direct control of HD-ZIPIII/KAN. PMID:26246448

  10. mTOR inhibition by rapamycin increases ceramide synthesis by promoting transforming growth factor-β1/Smad signaling in the skin.

    PubMed

    Yamane, Takumi; Muramatsu, Aimi; Yoshino, Sawako; Matsui, Sho; Shimura, Mari; Tsujii, Yoshimasa; Iwatsuki, Ken; Kobayashi-Hattori, Kazuo; Oishi, Yuichi

    2016-04-01

    Although mammalian target of rapamycin (mTOR) mediates a wide variety of biological functions, little information is available on the effect of mTOR on the functions of skin cells. In this study, we investigated effects of mTOR inhibition by rapamycin on ceramide synthesis in the skin of rats and human keratinocytes and its regulatory mechanisms. The phosphorylation of p70 S6 kinase, which indicates mTOR activation, was induced in the skin of rats fed a high-fat diet, but this abnormality was reversed by supplementation with rapamycin. Ceramide levels and the mRNA levels of serine palmitoyltransferase (SPT) and transforming growth factor (TGF)-β1 were suppressed in the skin of rats fed high-fat diets, but this abnormality was reversed by supplementation with rapamycin. TGF-β1-induced SPT mRNA expression was blocked by SB525334, an inhibitor of TGF-β1-induced Smad2/3 nuclear localization, in human keratinocytes. Rapamycin-induced SPT mRNA expression was blocked by an anti-TGF-β1 antibody or SB525334 in human keratinocytes. These results show that mTOR inhibition by rapamycin increases ceramide synthesis by promoting TGF-β1/Smad signaling in the skin. PMID:27239444

  11. Hypoxic inactivation of glycogen synthase kinase-3β promotes gastric tumor growth and angiogenesis by facilitating hypoxia-inducible factor-1 signaling.

    PubMed

    Ko, Young San; Cho, Sung Jin; Park, Jinju; Choi, Yiseul; Lee, Jae-Seon; Youn, Hong-Duk; Kim, Woo Ho; Kim, Min A; Park, Jong-Wan; Lee, Byung Lan

    2016-09-01

    Since the molecular mechanism of hypoxic adaptation in cancer cells is cell-type specific, we investigated whether glycogen synthase kinase-3β (GSK-3β) activation is involved in hypoxia-induced gastric tumor promotion. Stable gastric cancer cell lines (SNU-638, SNU-484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild-type GSK-3β (WT-GSK-3β) or kinase-dead mutant of GSK-3β (KD-GSK-3β) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK-3β activation in gastric cancer cells. Cell viability and the expressions of HIF-1α protein and VEGF mRNA in gastric cancer cells were higher in KD-GSK-3β transfectants than in WT-GSK-3β transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF-1α activation, and VEGF expression were higher in KD-GSK-3β tumors than in WT-GSK-3β tumors in vivo. In addition, the expression of hypoxia-induced HIF-1α protein was regulated by GSK-3β at the translational level. Our data suggest that GSK-3β is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF-1α/VEGF signaling pathway. PMID:27365055

  12. Meta-Analysis of Arabidopsis KANADI1 Direct Target Genes Identifies a Basic Growth-Promoting Module Acting Upstream of Hormonal Signaling Pathways1[OPEN

    PubMed Central

    Xie, Yakun; Straub, Daniel; Eguen, Tenai; Brandt, Ronny; Stahl, Mark; Martínez-García, Jaime F.; Wenkel, Stephan

    2015-01-01

    An intricate network of antagonistically acting transcription factors mediates the formation of a flat leaf lamina of Arabidopsis (Arabidopsis thaliana) plants. In this context, members of the class III homeodomain leucine zipper (HD-ZIPIII) transcription factor family specify the adaxial domain (future upper side) of the leaf, while antagonistically acting KANADI transcription factors determine the abaxial domain (future lower side). Here, we used a messenger RNA sequencing approach to identify genes regulated by KANADI1 (KAN1) and subsequently performed a meta-analysis combining our data sets with published genome-wide data sets. Our analysis revealed that KAN1 acts upstream of several genes encoding auxin biosynthetic enzymes. When exposed to shade, we found three YUCCA genes, YUC2, YUC5, and YUC8, to be transcriptionally up-regulated, which correlates with an increase in the levels of free auxin. When ectopically expressed, KAN1 is able to transcriptionally repress these three YUC genes and thereby block shade-induced auxin biosynthesis. Consequently, KAN1 is able to strongly suppress shade-avoidance responses. Taken together, we hypothesize that HD-ZIPIII/KAN form the basis of a basic growth-promoting module. Hypocotyl extension in the shade and outgrowth of new leaves both involve auxin synthesis and signaling, which are under the direct control of HD-ZIPIII/KAN. PMID:26246448

  13. Involvement of the salicylic acid signaling pathway in the systemic resistance induced in Arabidopsis by plant growth-promoting fungus Fusarium equiseti GF19-1.

    PubMed

    Kojima, Hanae; Hossain, Md Motaher; Kubota, Mayumi; Hyakumachi, Mitsuro

    2013-01-01

    Plant growth-promoting fungi (PGPF) are effective biocontrol agents for a number of soil-borne diseases and are known for their ability to trigger induced systemic resistance (ISR). In this study, we investigated the mechanisms triggered by PGPF Fusarium equiseti GF19-1, which is known to increase pathogen resistance in plants, by using GF19-1 spores and the culture filtrate (CF) to treat the roots of Arabidopsis thaliana. Subsequently, the leaves were challenged with Pseudomonas syringae pv tomato DC3000 (Pst) bacteria. Arabidopsis plants treated with GF19-1 spores or the CF elicited ISR against the Pst pathogen, resulting in a restriction of disease severity and suppression of pathogen proliferation. Examination of ISR in various signaling mutants and transgenic plants showed that GF19-1-induced protection was observed in the jasmonate response mutant jar1 and the ethylene response mutant etr1, whereas it was blocked in Arabidopsis plants expressing the NahG transgene or demonstrating a disruption of the NPR1 gene (npr1). Analysis of systemic gene expression revealed that GF19-1 modulates the expression of salicylic acid (SA)-responsive PR-1, PR-2, and PR-5 genes. Moreover, transient accumulation of SA was observed in GF19-1-treated plant, whereas the level was further enhanced after Pst infection of GF19-1-pretreated plants, indicating that accumulation of SA was potentiated when Arabidopsis plants were primed for disease resistance by GF19-1. In conclusion, these findings imply that the induced protective effect conferred by F. equiseti GF19-1 against the leaf pathogen Pst requires responsiveness to an SA-dependent pathway. PMID:23728333

  14. Syndecan-2 Exerts Antifibrotic Effects by Promoting Caveolin-1–mediated Transforming Growth Factor-β Receptor I Internalization and Inhibiting Transforming Growth Factor-β1 Signaling

    PubMed Central

    Shi, Yuanyuan; Gochuico, Bernadette R.; Yu, Guoying; Tang, Xiaomeng; Osorio, Juan C.; Fernandez, Isis E.; Risquez, Cristobal F.; Patel, Avignat S.; Shi, Ying; Wathelet, Marc G.; Goodwin, Andrew J.; Haspel, Jeffrey A.; Ryter, Stefan W.; Billings, Eric M.; Kaminski, Naftali; Morse, Danielle

    2013-01-01

    Rationale: Alveolar transforming growth factor (TGF)-β1 signaling and expression of TGF-β1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-β receptor TβRI inhibits TGF-β signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-β1 signaling in alveolar epithelial cells. Methods: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2–dependent changes in epithelial cell TGF-β1 signaling, TGF-β1, and TβRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. Measurements and Main Results: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting TGF-β1 signaling and downstream expression of TGF-β1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1–dependent internalization of TGF-β1 and TβRI in alveolar epithelial cells, which inhibited TGF-β1 signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. Conclusions: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting caveolin-1–dependent TGF-β1 and TβRI internalization and inhibiting TGF-β1 signaling in alveolar epithelial

  15. Amino Acids and TOR Signaling Promote Prothoracic Gland Growth and the Initiation of Larval Molts in the Tobacco Hornworm Manduca sexta

    PubMed Central

    Kemirembe, Karen; Liebmann, Kate; Bootes, Abigail; Smith, Wendy A.; Suzuki, Yuichiro

    2012-01-01

    Molting in arthropods is orchestrated by a series of endocrine changes that occur towards the end of an instar. However, little is understood about the mechanisms that trigger these endocrine changes. Here, nutritional inputs were manipulated to investigate the minimal nutritional inputs required for a Manduca sexta larva to initiate a molt. Amino acids were found to be necessary for a larva to molt, indicating the involvement of an amino acid sensitive pathway. Feeding rapamycin, an inhibitor of the target of rapamycin (TOR) signaling, delayed the onset of a molt and resulted in abnormally larger larvae. Rapamycin also suppressed the growth of the prothoracic glands relative to the whole body growth, and this was accompanied by suppression of ecdysone production and secretion. Higher doses of rapamycin also slowed the growth rate, indicating that TOR signaling also plays a role in systemic growth. TOR signaling therefore couples the nutritional status of the larva to the endocrine system to regulate the timing of a molt. PMID:22984508

  16. Human placental extract exerts hair growth-promoting effects through the GSK-3β signaling pathway in human dermal papilla cells.

    PubMed

    Kwon, Tae-Rin; Oh, Chang Taek; Choi, Eun Ja; Park, Hye Min; Han, Hae Jung; Ji, Hyi Jeong; Kim, Beom Joon

    2015-10-01

    Human placental extract (HPE) is widely used in Korea to relieve fatigue. However, its effects on human dermal papilla cells (hDPCs) remain unknown. In the present study, in an effort to develop novel therapies to promote hair growth, we screened HPE. We demonstrate that HPE has hair growth‑promoting activities and induces β‑catenin expression through the inhibition of glycogen synthase kinase‑3β (GSK‑3β) by phosphorylation in hDPCs. Treatment with HPE significantly increased the viability of the hDPCs in a concentration‑dependent manner, as shown by bromodeoxyuridine (BrdU) assay. HPE also significantly increased the alkaline phosphatase (ALP) expression levels. The increased β‑catenin levels and the inhibition of GSK‑3β (Ser9) by phosphorylation suggested that HPE promoted the hair-inductive capacity of hDPCs. We compared the effects of treatment with HPE alone and treatment with HPE in conjunction with minoxidil (MXD). We found that HPE plus MXD effectively inhibited GSK‑3β by phosphorylation (Ser9) in the hDPCs. Moreover, we demonstrated that HPE was effective in inducing root hair elongation in rat vibrissa hair follicles, and that treatment with HPE led to a delay in catagen progression. Overall, our findings suggest that HPE promotes hair growth and may thus provide the basis of a novel therapeutic strategy for the clinical treatment of hair loss. PMID:26311045

  17. Interdependent epidermal growth factor receptor signalling and trafficking.

    PubMed

    Jones, Sylwia; Rappoport, Joshua Z

    2014-06-01

    Epidermal growth factor (EGF) receptor (EGFR) signalling regulates diverse cellular functions, promoting cell proliferation, differentiation, migration, cell growth and survival. EGFR signalling is critical during embryogenesis, in particular in epithelial development, and disruption of the EGFR gene results in epithelial immaturity and perinatal death. EGFR signalling also functions during wound healing responses through accelerating wound re-epithelialisation, inducing cell migration, proliferation and angiogenesis. Upregulation of EGFR signalling is often observed in carcinomas and has been shown to promote uncontrolled cell proliferation and metastasis. Therefore aberrant EGFR signalling is a common target for anticancer therapies. Various reports indicate that EGFR signalling primarily occurs at the plasma membrane and EGFR degradation following endocytosis greatly attenuates signalling. Other studies argue that EGFR internalisation is essential for complete activation of downstream signalling cascades and that endosomes can serve as signalling platforms. The aim of this review is to discuss current understanding of intersection between EGFR signalling and trafficking. PMID:24681003

  18. A synthetic mechano-growth factor E peptide promotes rat tenocyte migration by lessening cell stiffness and increasing F-actin formation via the FAK-ERK1/2 signaling pathway

    SciTech Connect

    Zhang, Bingyu; Luo, Qing; Mao, Xinjian; Xu, Baiyao; Yang, Li; Ju, Yang; Song, Guanbin

    2014-03-10

    Tendon injuries are common in sports and are frequent reasons for orthopedic consultations. The management of damaged tendons is one of the most challenging problems in orthopedics. Mechano-growth factor (MGF), a recently discovered growth repair factor, plays positive roles in tissue repair through the improvement of cell proliferation and migration and the protection of cells against injury-induced apoptosis. However, it remains unclear whether MGF has the potential to accelerate tendon repair. We used a scratch wound assay in this study to demonstrate that MGF-C25E (a synthetic mechano-growth factor E peptide) promotes the migration of rat tenocytes and that this promotion is accompanied by an elevation in the expression of the following signaling molecules: focal adhesion kinase (FAK) and extracellular signal regulated kinase1/2 (ERK1/2). Inhibitors of the FAK and ERK1/2 pathways inhibited the MGF-C25E-induced tenocyte migration, indicating that MGF-C25E promotes tenocyte migration through the FAK-ERK1/2 signaling pathway. The analysis of the mechanical properties showed that the Young's modulus of tenocytes was decreased through treatment of MGF-C25E, and an obvious formation of pseudopodia and F-actin was observed in MGF-C25E-treated tenocytes. The inhibition of the FAK or ERK1/2 signals restored the decrease in Young's modulus and inhibited the formation of pseudopodia and F-actin. Overall, our study demonstrated that MGF-C25E promotes rat tenocyte migration by lessening cell stiffness and increasing pseudopodia formation via the FAK-ERK1/2 signaling pathway. - Highlights: • Mechano-growth factor E peptide (MGF-C25E) promotes migration of rat tenocytes. • MGF-C25E activates the FAK-ERK1/2 pathway in rat tenocytes. • MGF-C25E induces the actin remodeling and the formation of pseudopodia, and decreases the stiffness in rat tenocytes. • MGF-C25E promotes tenocyte migration via altering stiffness and forming pseudopodia by the activation of the FAK-ERK1

  19. Potential role of human growth hormone in melanoma growth promotion.

    PubMed

    Handler, Marc Z; Ross, Andrew L; Shiman, Michael I; Elgart, George W; Grichnik, James M

    2012-10-01

    BACKGROUND Human growth hormone (HGH) and insulin-like growth factor-1 (IGF-1) have been shown to play a role in the malignant transformation and progression of a variety of cancers. HGH is also known to upregulate molecular signaling pathways implicated in the pathogenesis of melanoma. Although HGH has previously been implicated in promoting the clinical growth of both benign and malignant melanocytic neoplasms, to our knowledge there are no conclusive studies demonstrating an increased risk of melanoma following HGH therapy. Nevertheless, there are reports of melanoma developing subsequent to HGH coadministered with either other hormones or following irradiation. OBSERVATION A 49-year-old white man presented with a new pigmented papule that was diagnosed as melanoma. The patient reported using HGH for 3 months prior to the diagnosis. His 51-year-old wife, who also was white, had also been using exogenous HGH for 3 months and had been diagnosed as having a melanoma 2 weeks prior. CONCLUSIONS Given the unlikelihood of 2 unrelated people developing melanoma within a short time span, it is reasonable to assume that a common environmental component (HGH or other shared exposure) contributed to the development of both melanomas. Because of the increased use of exogenous HGH as an antiaging agent, it is important to be aware of the growth-promoting effects of this hormone. Until better data are available that determines the true risk of exogenous HGH, its use as an antiaging agent merits increased surveillance. PMID:23069955

  20. The inter-kingdom volatile signal indole promotes root development by interfering with auxin signalling.

    PubMed

    Bailly, Aurélien; Groenhagen, Ulrike; Schulz, Stefan; Geisler, Markus; Eberl, Leo; Weisskopf, Laure

    2014-12-01

    Recently, emission of volatile organic compounds (VOCs) has emerged as a mode of communication between bacteria and plants. Although some bacterial VOCs that promote plant growth have been identified, their underlying mechanism of action is unknown. Here we demonstrate that indole, which was identified using a screen for Arabidopsis growth promotion by VOCs from soil-borne bacteria, is a potent plant-growth modulator. Its prominent role in increasing the plant secondary root network is mediated by interfering with the auxin-signalling machinery. Using auxin reporter lines and classic auxin physiological and transport assays we show that the indole signal invades the plant body, reaches zones of auxin activity and acts in a polar auxin transport-dependent bimodal mechanism to trigger differential cellular auxin responses. Our results suggest that indole, beyond its importance as a bacterial signal molecule, can serve as a remote messenger to manipulate plant growth and development. PMID:25227998

  1. Downregulated MicroRNA-200a in Meningiomas Promotes Tumor Growth by Reducing E-Cadherin and Activating the Wnt/β-Catenin Signaling Pathway▿

    PubMed Central

    Saydam, Okay; Shen, Yiping; Würdinger, Thomas; Senol, Ozlem; Boke, Elvan; James, Marianne F.; Tannous, Bakhos A.; Stemmer-Rachamimov, Anat O.; Yi, Ming; Stephens, Robert M.; Fraefel, Cornel; Gusella, James F.; Krichevsky, Anna M.; Breakefield, Xandra O.

    2009-01-01

    Meningiomas, one of the most common human brain tumors, are derived from arachnoidal cells associated with brain meninges, are usually benign, and are frequently associated with neurofibromatosis type 2. Here, we define a typical human meningioma microRNA (miRNA) profile and characterize the effects of one downregulated miRNA, miR-200a, on tumor growth. Elevated levels of miR-200a inhibited meningioma cell growth in culture and in a tumor model in vivo. Upregulation of miR-200a decreased the expression of transcription factors ZEB1 and SIP1, with consequent increased expression of E-cadherin, an adhesion protein associated with cell differentiation. Downregulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of β-catenin and cyclin D1 involved in cell proliferation. miR-200a was found to directly target β-catenin mRNA, thereby inhibiting its translation and blocking Wnt/β-catenin signaling, which is frequently involved in cancer. A direct correlation was found between the downregulation of miR-200a and the upregulation of β-catenin in human meningioma samples. Thus, miR-200a appears to act as a multifunctional tumor suppressor miRNA in meningiomas through effects on the E-cadherin and Wnt/β-catenin signaling pathways. This reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas. PMID:19703993

  2. The future of growth-promoting therapy.

    PubMed

    Rosenfeld, Ron G

    2016-06-01

    Growth hormone (GH) has been in use for 50years in children with short stature. Recent developments suggest that our traditional approaches to growth-promoting therapy will be challenged in the following areas. PMID:26654694

  3. FGF signalling regulates bone growth through autophagy.

    PubMed

    Cinque, Laura; Forrester, Alison; Bartolomeo, Rosa; Svelto, Maria; Venditti, Rossella; Montefusco, Sandro; Polishchuk, Elena; Nusco, Edoardo; Rossi, Antonio; Medina, Diego L; Polishchuk, Roman; De Matteis, Maria Antonietta; Settembre, Carmine

    2015-12-10

    Skeletal growth relies on both biosynthetic and catabolic processes. While the role of the former is clearly established, how the latter contributes to growth-promoting pathways is less understood. Macroautophagy, hereafter referred to as autophagy, is a catabolic process that plays a fundamental part in tissue homeostasis. We investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation and extracellular matrix (ECM) deposition in growth plates. Here we show that autophagy is induced in growth-plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene 7 (Atg7) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (PC2) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, post-natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18(-/-) embryos, while Fgf18(+/-) heterozygous and Fgfr4(-/-) mice fail to induce autophagy during post-natal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18(+/-) and Fgfr4(-/-) phenotypes can be rescued in vivo by pharmacological activation of autophagy, pointing to autophagy as a novel effector of FGF signalling in bone. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes. PMID:26595272

  4. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma.

    PubMed

    Peng, Hong; Zhang, Qiuyang; Li, Jiali; Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yubin; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui; Kuang, Ming

    2016-03-29

    Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC. PMID:26967384

  5. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma

    PubMed Central

    Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yubin; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui; Kuang, Ming

    2016-01-01

    Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC. PMID:26967384

  6. The Systemic Acquired Resistance Regulator OsNPR1 Attenuates Growth by Repressing Auxin Signaling through Promoting IAA-Amido Synthase Expression.

    PubMed

    Li, Xiaozun; Yang, Dong-Lei; Sun, Li; Li, Qun; Mao, Bizeng; He, Zuhua

    2016-09-01

    Systemic acquired resistance is a long-lasting and broad-spectrum disease resistance to pathogens. Our previous study demonstrated that overexpression of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (OsNPR1), a master gene for systemic acquired resistance in rice (Oryza sativa), greatly enhanced resistance to bacterial blight caused by Xanthomonas oryzae pv oryzae However, the growth and development of the OsNPR1 overexpression (OsNPR1-OX) plants were restrained, and the mechanism remained elusive. In this study, we dissected the OsNPR1-induced growth inhibition. We found that the OsNPR1-OX lines displayed phenotypes mimicking auxin-defective mutants, with decreases in root system, seed number and weight, internode elongation, and tiller number. Whole-genome expression analysis revealed that genes related to the auxin metabolism and signaling pathway were differentially expressed between the OsNPR1-OX and wild-type plants. Consistently, the indole-3-acetic acid (IAA) content was decreased and the auxin distribution pattern was altered in OsNPR1-OX plants. Importantly, we found that some GH3 family members, in particular OsGH3.8 coding IAA-amido synthetase, were constitutively up-regulated in OsNPR1-OX plants. Decreased OsGH3.8 expression by RNA interference could partially restore IAA level and largely rescue the restrained growth and development phenotypes but did not affect the disease resistance of OsNPR1-OX plants. Taken together, we revealed that OsNPR1 affects rice growth and development by disrupting the auxin pathway at least partially through indirectly up-regulating OsGH3.8 expression. PMID:27378815

  7. Interleukin17A Promotes Postoperative Cognitive Dysfunction by Triggering β-Amyloid Accumulation via the Transforming Growth Factor-β (TGFβ)/Smad Signaling Pathway

    PubMed Central

    Tian, Ayong; Ma, Hong; Zhang, Rongwei; Tan, Wenfei; Wang, Xiaolong; Wu, Binyang; Wang, Jun; Wan, Chengfu

    2015-01-01

    Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer’s disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1–42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in Aβ1–42 and TGFβ/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGFβ/Smad activation and Aβ1–42 expression were reversed by IL17A receptor small interfering RNA and a TGFβ receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1–42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD. PMID:26509545

  8. Hydrogen peroxide inhibits transforming growth factor-β1-induced cell cycle arrest by promoting Smad3 linker phosphorylation through activation of Akt-ERK1/2-linked signaling pathway.

    PubMed

    Choi, Jiyeon; Park, Seong Ji; Jo, Eun Ji; Lee, Hui-Young; Hong, Suntaek; Kim, Seong-Jin; Kim, Byung-Chul

    2013-06-14

    Hydrogen peroxide (H2O2) functions as a second messenger in growth factor receptor-mediated intracellular signaling cascade and is tumorigenic by virtue of its ability to promote cell proliferation; however, the mechanisms underlying the growth stimulatory action of H2O2 are less understood. Here we report an important mechanism for antagonistic effects of H2O2 on growth inhibitory response to transforming growth factor-β1 (TGF-β1). In Mv1Lu and HepG2 cells, pretreatment of H2O2 (0.05-0.2 mM) completely blocked TGF-β1-mediated induction of p15(INK4B) expression and increase of its promoter activity. Interestingly, H2O2 selectively suppressed the transcriptional activation potential of Smad3, not Smad2, in the absence of effects on TGF-β1-induced phosphorylation of the COOH-tail SSXS motif of Smad3 and its nuclear translocation. Mechanism studies showed that H2O2 increases the phosphorylation of Smad3 at the middle linker region in a concentration- and time-dependent manner and this effect is mediated by activation of extracellular signal-activated kinase 1/2 through Akt. Furthermore, expression of a mutant Smad3 in which linker phosphorylation sites were ablated significantly abrogated the inhibitory effects of H2O2 on TGF-β1-induced increase of p15(INK4B)-Luc reporter activity and blockade of cell cycle progression from G1 to S phase. These findings for the first time define H2O2 as a signaling molecule that modulate Smad3 linker phosphorylation and its transcriptional activity, thus providing a potential mechanism whereby H2O2 antagonizes the cytostatic function of TGF-β1. PMID:23685151

  9. Noisy signaling through promoter logic gates

    NASA Astrophysics Data System (ADS)

    Gerstung, Moritz; Timmer, Jens; Fleck, Christian

    2009-01-01

    We study the influence of noisy transcription factor signals on cis-regulatory promoter elements. These elements process the probability of binary binding events analogous to computer logic gates. At equilibrium, this probability is given by the so-called input function. We show that transcription factor noise causes deviations from the equilibrium value due to the nonlinearity of the input function. For a single binding site, the correction is always negative resulting in an occupancy below the mean-field level. Yet for more complex promoters it depends on the correlation of the transcription factor signals and the geometry of the input function. We present explicit solutions for the basic types of AND and OR gates. The correction size varies among these different types of gates and signal types, mainly being larger in AND gates and for correlated fluctuations. In all cases we find excellent agreement between the analytical results and numerical simulations. We also study the E. coli Lac operon as an example of an AND NOR gate. We present a consistent mathematical method that allows one to separate different sources of noise and quantifies their effect on promoter occupation. A surprising result of our analysis is that Poissonian molecular fluctuations, in contrast to external fluctuations, do no contribute to the correction.

  10. ANXA3/JNK Signaling Promotes Self-Renewal and Tumor Growth, and Its Blockade Provides a Therapeutic Target for Hepatocellular Carcinoma

    PubMed Central

    Tong, Man; Fung, Tsun-Ming; Luk, Steve T.; Ng, Kai-Yu; Lee, Terence K.; Lin, Chi-Ho; Yam, Judy W.; Chan, Kwok Wah; Ng, Fai; Zheng, Bo-Jian; Yuan, Yun-Fei; Xie, Dan; Lo, Chung-Mau; Man, Kwan; Guan, Xin-Yuan; Ma, Stephanie

    2015-01-01

    Summary Frequent tumor relapse in hepatocellular carcinoma (HCC) has been commonly attributed to the presence of residual cancer stem cells (CSCs) after conventional treatments. We have previously identified and characterized CD133 to mark a specific CSC subset in HCC. In the present study, we found endogenous and secretory annexin A3 (ANXA3) to play pivotal roles in promoting cancer and stem cell-like features in CD133+ liver CSCs through a dysregulated JNK pathway. Blockade of ANXA3 with an anti-ANXA3 monoclonal antibody in vitro as well as in human HCC xenograft models resulted in a significant reduction in tumor growth and self-renewal. Clinically, ANXA3 expression in HCC patient sera closely associated with aggressive clinical features. Our results suggest that ANXA3 can serve as a novel diagnostic biomarker and that the inhibition of ANXA3 may be a viable therapeutic option for the treatment of CD133+ liver-CSC-driven HCC. PMID:26095609

  11. Chitin promotes Mycobacterium ulcerans growth.

    PubMed

    Sanhueza, Daniel; Chevillon, Christine; Colwell, Rita; Babonneau, Jérémie; Marion, Estelle; Marsollier, Laurent; Guégan, Jean-François

    2016-06-01

    Mycobacterium ulcerans(MU) is the causative agent of Buruli ulcer, an emerging human infectious disease. However, both the ecology and life cycle of MU are poorly understood. The occurrence of MU has been linked to the aquatic environment, notably water bodies affected by human activities. It has been hypothesized that one or a combination of environmental factor(s) connected to human activities could favour growth of MU in aquatic systems. Here, we testedin vitrothe growth effect of two ubiquitous polysaccharides and five chemical components on MU at concentration ranges shown to occur in endemic regions. Real-time PCR showed that chitin increased MU growth significantly providing a nutrient source or environmental support for thebacillus, thereby, providing a focus on the association between MU and aquatic arthropods. Aquatic environments with elevated population of arthropods provide increased chitin availability and, thereby, enhanced multiplication of MU. If calcium very slightly enhanced MU growth, iron, zinc, sulphate and phosphate did not stimulate MU growth, and at the concentration ranges of this study would limit MU population in natural ecosystems. PMID:27020062

  12. Hydrogen peroxide inhibits transforming growth factor-β1-induced cell cycle arrest by promoting Smad3 linker phosphorylation through activation of Akt-ERK1/2-linked signaling pathway

    SciTech Connect

    Choi, Jiyeon; Park, Seong Ji; Jo, Eun Ji; Lee, Hui-Young; Hong, Suntaek; Kim, Seong-Jin; Kim, Byung-Chul

    2013-06-14

    Highlights: •H{sub 2}O{sub 2} inhibits TGF-β1-induced cell cycle arrest. •H{sub 2}O{sub 2} induces Smad3 linker phosphorylation through Akt-ERK1/2 pathway. •H{sub 2}O{sub 2}-mediated suppression of TGF-β signal requires Smad3 linker phosphorylation. •This is a first report about interplay between H{sub 2}O{sub 2} and growth inhibition pathway. -- Abstract: Hydrogen peroxide (H{sub 2}O{sub 2}) functions as a second messenger in growth factor receptor-mediated intracellular signaling cascade and is tumorigenic by virtue of its ability to promote cell proliferation; however, the mechanisms underlying the growth stimulatory action of H{sub 2}O{sub 2} are less understood. Here we report an important mechanism for antagonistic effects of H{sub 2}O{sub 2} on growth inhibitory response to transforming growth factor-β1 (TGF-β1). In Mv1Lu and HepG2 cells, pretreatment of H{sub 2}O{sub 2} (0.05–0.2 mM) completely blocked TGF-β1-mediated induction of p15{sup INK4B} expression and increase of its promoter activity. Interestingly, H{sub 2}O{sub 2} selectively suppressed the transcriptional activation potential of Smad3, not Smad2, in the absence of effects on TGF-β1-induced phosphorylation of the COOH-tail SSXS motif of Smad3 and its nuclear translocation. Mechanism studies showed that H{sub 2}O{sub 2} increases the phosphorylation of Smad3 at the middle linker region in a concentration- and time-dependent manner and this effect is mediated by activation of extracellular signal-activated kinase 1/2 through Akt. Furthermore, expression of a mutant Smad3 in which linker phosphorylation sites were ablated significantly abrogated the inhibitory effects of H{sub 2}O{sub 2} on TGF-β1-induced increase of p15{sup INK4B}-Luc reporter activity and blockade of cell cycle progression from G1 to S phase. These findings for the first time define H{sub 2}O{sub 2} as a signaling molecule that modulate Smad3 linker phosphorylation and its transcriptional activity, thus providing

  13. A role for TOR complex 2 signaling in promoting autophagy.

    PubMed

    Vlahakis, Ariadne; Powers, Ted

    2014-01-01

    The conserved target of rapamycin (TOR) kinase is a central regulator of cell growth in response to nutrient availability. TOR forms 2 structurally and functionally distinct complexes, TORC1 and TORC2, and negatively regulates autophagy via TORC1. Here we demonstrate TOR also operates independently through the TORC2 signaling pathway to promote autophagy upon amino acid limitation. Under these conditions, TORC2, through its downstream target kinase Ypk1, inhibits the Ca(2+)- and Cmd1/calmodulin-dependent phosphatase, calcineurin, to enable the activation of the amino acid-sensing EIF2S1/eIF2α kinase, Gcn2, and promote autophagy. Thus TORC2 signaling regulates autophagy in a pathway distinct from TORC1 to provide a tunable response to the cellular metabolic state. PMID:25426890

  14. Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells.

    PubMed

    Liu, Xiujuan; Hong, Quan; Wang, Zhen; Yu, Yanyan; Zou, Xin; Xu, Lihong

    2016-02-01

    Renal fibrosis is a progressive pathological change characterized by tubular cell apoptosis, tubulointerstitial fibroblast proliferation, and excessive deposition of extracellular matrix (ECM). miR-21 has been implicated in transforming growth factor-β (TGF-β)-stimulated tissue fibrosis. Recent studies showed that sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) are also critical for TGF-β-stimulated tissue fibrosis; however, it is not clear whether SphK/S1P interacts with miR-21 or not. In this study, we hypothesized that SphK/S1P signaling is linked to upregulation of miR-21 by TGF-β. To verify this hypothesis, we first determined that miR-21 was highly expressed in renal tubular epithelial cells (TECs) stimulated with TGF-β by using qRT-PCR and Northern blotting. Simultaneously, inhibition of miR-21, mediated by the corresponding antimir, markedly decreased the expression and deposition of type I collagen, fibronectin (Fn), cysteine-rich protein 61 (CCN1), α-smooth muscle actin, and fibroblast-specific protein1 in TGF-β-treated TECs. ELISA and qRT-PCR were used to measure the S1P and SphK1 levels in TECs. S1P production was induced by TGF-β through activation of SphK1. Furthermore, it was observed that TGF-β-stimulated upregulation of miR-21 was abolished by SphK1 siRNA and was restored by the addition of exogenous S1P. Blocking S1PR2 also inhibited upregulation of miR-21. Additionally, miR-21 overexpression attenuated the repression of TGF-β-stimulated ECM deposition and epithelial-mesenchymal transition by SphK1 and S1PR2 siRNA. In summary, our study demonstrates a link between SphK1/S1P and TGF-β-induced miR-21 in renal TECs and may represent a novel therapeutic target in renal fibrosis. PMID:26376826

  15. Signals to promote myelin formation and repair

    PubMed Central

    Taveggia, Carla; Feltri, Maria Laura; Wrabetz, Lawrence

    2011-01-01

    The myelin sheath wraps large axons in both the CNS and the PNS, and is a key determinant of efficient axonal function and health. Myelin is targeted in a series of diseases, notably multiple sclerosis (MS). In MS, demyelination is associated with progressive axonal damage, which determines the level of patient disability. Few treatments are available for combating myelin damage in MS and related disorders. These treatments, which largely comprise anti-inflammatory drugs, only show limited efficacy in subsets of patients. More-effective treatment of myelin disorders will probably result from early intervention with combinatorial therapies that target inflammation and other processes—for example, signaling pathways that promote remyelination. Indeed, evidence suggests that such pathways might be impaired in pathology and, hence, contribute to the failure of remyelination in such diseases. In this article, we review the molecular basis of signaling pathways that regulate myelination in the CNS and PNS with a focus on differentiation of myelinating glia. We also discuss factors such as extracellular molecules that act as modulators of these pathways. Finally, we consider the few preclinical and clinical trials of agents that augment this signaling. PMID:20404842

  16. NMU signaling promotes endometrial cancer cell progression by modulating adhesion signaling.

    PubMed

    Lin, Ting-Yu; Wu, Fang-Ju; Chang, Chia-Lin; Li, Zhongyou; Luo, Ching-Wei

    2016-03-01

    Neuromedin U (NMU) was originally named based on its strong uterine contractile activity, but little is known regarding its signaling/functions in utero. We identified that NMU and one of its receptors, NMUR2, are not only present in normal uterine endometrium but also co-expressed in endometrial cancer tissues, where the NMU level is correlated with the malignant grades and survival of patients. Cell-based assays further confirmed that NMU signaling can promote cell motility and proliferation of endometrial cancer cells derived from grade II tumors. Activation of NMU pathway in these endometrial cancer cells is required in order to sustain expression of various adhesion molecules, such as CD44 and integrin alpha1, as well as production of their corresponding extracellular matrix ligands, hyaluronan and collagen IV; it also increased the activity of SRC and its downstream proteins RHOA and RAC1. Thus, it is concluded that NMU pathway positively controls the adhesion signaling-SRC-Rho GTPase axis in the tested endometrial cancer cells and that changes in cell motility and proliferation can occur when there is manipulation of NMU signaling in these cells either in vitro or in vivo. Intriguingly, this novel mechanism also explains how NMU signaling promotes the EGFR-driven and TGFβ receptor-driven mesenchymal transitions. Through the above axis, NMU signaling not only can promote malignancy of the tested endometrial cancer cells directly, but also helps these cells to become more sensitive to niche growth factors in their microenvironment. PMID:26849234

  17. NMU signaling promotes endometrial cancer cell progression by modulating adhesion signaling

    PubMed Central

    Lin, Ting-Yu; Wu, Fang-Ju; Chang, Chia-Lin; Li, Zhongyou; Luo, Ching-Wei

    2016-01-01

    Neuromedin U (NMU) was originally named based on its strong uterine contractile activity, but little is known regarding its signaling/functions in utero. We identified that NMU and one of its receptors, NMUR2, are not only present in normal uterine endometrium but also co-expressed in endometrial cancer tissues, where the NMU level is correlated with the malignant grades and survival of patients. Cell-based assays further confirmed that NMU signaling can promote cell motility and proliferation of endometrial cancer cells derived from grade II tumors. Activation of NMU pathway in these endometrial cancer cells is required in order to sustain expression of various adhesion molecules, such as CD44 and integrin alpha1, as well as production of their corresponding extracellular matrix ligands, hyaluronan and collagen IV; it also increased the activity of SRC and its downstream proteins RHOA and RAC1. Thus, it is concluded that NMU pathway positively controls the adhesion signaling-SRC-Rho GTPase axis in the tested endometrial cancer cells and that changes in cell motility and proliferation can occur when there is manipulation of NMU signaling in these cells either in vitro or in vivo. Intriguingly, this novel mechanism also explains how NMU signaling promotes the EGFR-driven and TGFβ receptor-driven mesenchymal transitions. Through the above axis, NMU signaling not only can promote malignancy of the tested endometrial cancer cells directly, but also helps these cells to become more sensitive to niche growth factors in their microenvironment. PMID:26849234

  18. 22-Oxocholestanes as plant growth promoters.

    PubMed

    Zeferino-Diaz, Reyna; Hilario-Martinez, J Ciciolil; Rodriguez-Acosta, Maricela; Sandoval-Ramirez, Jesus; Fernandez-Herrera, Maria A

    2015-06-01

    The spirostanic steroidal side-chain of diosgenin and hecogenin was modified to produce 22-oxocholestane derivatives. This type of side-chain was obtained in good yields through a straightforward four-step pathway. These compounds show potent brassinosteroid-like growth promoting activity evaluated via the rice lamina joint inclination bioassay. This is the first report of steroidal skeletons bearing the 22-oxocholestane side-chain and preserving the basic structure (A-D rings) from their corresponding parent compounds acting as plant growth promoters. PMID:25795152

  19. Light signaling and the phytohormonal regulation of shoot growth.

    PubMed

    Kurepin, Leonid V; Pharis, Richard P

    2014-12-01

    Shoot growth of dicot plants is rigorously controlled by the interactions of environmental cues with several groups of phytohormones. The signaling effects of light on shoot growth are of special interest, as both light irradiance and light quality change rapidly throughout the day, causing profound changes in stem elongation and leaf area growth. Among the several dicot species examined, we have focused on sunflower (Helianthus annuus L.) because its shoots are robust and their growth is highly plastic. Sunflower shoots thus constitute an ideal tissue for assessing responses to both light irradiance and light quality signals. Herein, we discuss the possible roles of gibberellins, auxin, ethylene, cytokinins and brassinosteroids in mediating the stem elongation and leaf area growth that is induced by shade light. To do this we uncoupled the plant's responses to changes in the red to far-red [R/FR] light ratio from its responses to changes in irradiance of photosynthetically active radiation [PAR]. Reducing each of R/FR light ratio and PAR irradiance results in increased sunflower stem elongation. However, the plant's response for leaf area growth differs considerably, with a low R/FR ratio generally promoting leaf area growth, whereas low irradiance PAR inhibits it. The increased stem elongation that occurs in response to lowering R/FR ratio and PAR irradiance is accomplished at the expense of leaf area growth. In effect, the low PAR irradiance signal overrides the low R/FR ratio signal in shade light's control of leaf growth and development. Three hormone groups, gibberellins, auxin and ethylene are directly involved in regulating these light-mediated shoot growth changes. Gibberellins and auxin function as growth promoters, with auxin likely acting as an up-regulator of gibberellin biosynthesis. Ethylene functions as a growth-inhibitor and probably interacts with gibberellins in regulating both stem and leaf growth of the sunflower shoot. PMID:25443853

  20. Shoot-derived abscisic acid promotes root growth.

    PubMed

    McAdam, Scott A M; Brodribb, Timothy J; Ross, John J

    2016-03-01

    The phytohormone abscisic acid (ABA) plays a major role in regulating root growth. Most work to date has investigated the influence of root-sourced ABA on root growth during water stress. Here, we tested whether foliage-derived ABA could be transported to the roots, and whether this foliage-derived ABA had an influence on root growth under well-watered conditions. Using both application studies of deuterium-labelled ABA and reciprocal grafting between wild-type and ABA-biosynthetic mutant plants, we show that both ABA levels in the roots and root growth in representative angiosperms are controlled by ABA synthesized in the leaves rather than sourced from the roots. Foliage-derived ABA was found to promote root growth relative to shoot growth but to inhibit the development of lateral roots. Increased root auxin (IAA) levels in plants with ABA-deficient scions suggest that foliage-derived ABA inhibits root growth through the root growth-inhibitor IAA. These results highlight the physiological and morphological importance, beyond the control of stomata, of foliage-derived ABA. The use of foliar ABA as a signal for root growth has important implications for regulating root to shoot growth under normal conditions and suggests that leaf rather than root hydration is the main signal for regulating plant responses to moisture. PMID:26514625

  1. In Scarcity and Abundance: Metabolic Signals Regulating Cell Growth

    PubMed Central

    Saad, Shady; Peter, Matthias

    2013-01-01

    Although nutrient availability is a major driver of cell growth, and continuous adaptation to nutrient supply is critical for the development and survival of all organisms, the molecular mechanisms of nutrient sensing are only beginning to emerge. Here, we highlight recent advances in the field of nutrient sensing and discuss arising principles governing how metabolism might regulate growth-promoting pathways. In addition, we discuss signaling functions of metabolic enzymes not directly related to their metabolic activity. PMID:23997189

  2. Promoting Angiogenesis via Manipulation of VEGF Responsiveness with Notch Signaling

    PubMed Central

    Cao, Lan; Arany, Praveen R.; Wang, Yuan-Shuo; Mooney, David J.

    2009-01-01

    Promoting angiogenesis via delivery of vascular endothelial growth factor (VEGF) and other angiogenic factors is both a potential therapy for cardiovascular diseases and a critical aspect for tissue regeneration. The recent demonstration that VEGF signaling is modulated by the Notch signaling pathway, however, suggests that inhibiting Notch signaling may enhance regional neovascularization, by altering the responsiveness of local endothelial cells to angiogenic stimuli. We tested this possibility with in vitro assays using human endothelial cells, as well as in a rodent hindlimb ischemia model. Treatment of cultured human endothelial cells with DAPT, a gamma secretase inhibitor, increased cell migration and sprout formation in response to VEGF stimulation with a biphasic dependence on DAPT concentration. Further, delivery of an appropriate combination of DAPT and VEGF from an injectable alginate hydrogel system into ischemic hindlimbs led to a faster recovery of blood flow than VEGF or DAPT alone; perfusion levels reached 80% of the normal level by week 4 with combined DAPT and VEGF delivery. Direct intramuscular or intraperitoneal injection of DAPT did not result in the same level of improvement, suggesting that appropriate presentation of DAPT (gel delivery) is important for its activity. DAPT delivery from the hydrogels also did not lead to any adverse side effects, in contrast to systemic introduction of DAPT. Altogether, these results suggest a new approach to promote angiogenesis by controlling Notch signaling, and may provide new options to treat patients with diseases that diminish angiogenic responsiveness. PMID:19481797

  3. IL-1β/NF-kb signaling promotes colorectal cancer cell growth through miR-181a/PTEN axis.

    PubMed

    Hai Ping, Pei; Feng Bo, Tan; Li, Liu; Nan Hui, Yu; Hong, Zhu

    2016-08-15

    To date, the role of miRNA in tumorigenesis has been largely reported. It was found that miR-181a may be involved in the tumorigenesis of colon cancer. The purpose of this study was to investigate the mechanism of miR-181a in colon cancer carcinogenesis. The expression levels of IL-1β, NF-κB (RelA), and miR-181a in colon cancer tissue were higher than that in normal control tissue when assessed by real-timePCR. In addition, it was found that IL-1β induced the expression of miR-181a. The expression of PTEN was regulated by IL-1β-stimulated miR-181a expression. In a PTEN reporter plasmid, miR-181a binding site mutations were introduced. By using a luciferase reporter assay, it was found that wild type reported activity was lower than that of the mutant registration system activity. Furthermore, a siRNA strategy was used to find that IL-1B regulates miR-181a expression via NF-κB and then regulates PTEN expression. Consequently, repression of PTEN by miR-181a promotes colon cancer cell proliferation. Taken together, our data support a critical role for NF-κB-dependent upregulation of miR-181a; this represents a new pathway for the repression of PTEN and the promotion of cell proliferation upon IL-1β induction. PMID:27264420

  4. Growth monitoring and the promotion of breastfeeding.

    PubMed

    Behague, D

    1993-12-01

    Recent studies evaluating the efficacy of growth monitoring programs have scrutinized their educational and preventive capabilities. Advocates claim that growth monitoring can be effective if communities and mothers are more actively involved in the process of weighing and measuring, and if the technology is understood by all as an aid for disease prevention and health promotion rather than as a 'curative' procedure. Others have argued that this theory is rarely possible to implement. The ways in which preventive growth monitoring can be made possible are still under exploration, given that the reasons for such deeply imbedded 'curative' expectations of growth monitoring are not fully understood. Any such understanding requires an analysis of growth monitoring within the context of the GOBI (growth monitoring, oral rehydration therapy, breastfeeding and immunization) child survival framework. To attain this type of understanding, a series of qualitative methodological techniques were used in a population of 50 mothers and several health care facilities in Pelotas, RS, Brazil, as a complement to pre-existing epidemiological data from the Center for Epidemiology at the Federal University of Pelotas. With a subsample of 15 mothers, intensive interviews and observations were specifically focused on: (1) mothers' understanding of growth monitoring, (2) breastfeeding practices and beliefs, (3) doctor-patient communication. Findings from this study suggest that, even in a program with widespread attendance and a relatively 'interactive' growth monitoring approach, the use of growth charts do little to promote duration or frequency of breastfeeding, and may even pay a role in the factors which deter women from choosing to breastfeed for longer durations or with greater frequency. We found that mothers' personal interpretations of the charts were representative of the larger socio-cultural and economic issues that affected their lives on a daily basis. Growth charts thus

  5. Inhibition of Transforming Growth Factor-β Receptor signaling promotes culture expansion of undifferentiated human Endometrial Mesenchymal Stem/stromal Cells

    PubMed Central

    Gurung, Shanti; Werkmeister, Jerome A.; Gargett, Caroline E.

    2015-01-01

    Human endometrial MSC (eMSC) are a novel source of MSC easily harvested from the highly regenerative uterine lining. We have developed protocols for eMSC isolation from single cell suspensions using magnetic bead-sorting using a perivascular marker antibody to SUSD2 and culture expansion in serum free medium (SFM). Similar to other MSC, eMSC spontaneously differentiate into fibroblasts during culture expansion decreasing their purity and efficacy. The aim of this study was to determine if A83-01, a TGF-β receptor inhibitor prevents eMSC differentiation in culture. SUSD2+ eMSC were cultured in SFM with bFGF/EGF in 5% O2/5% CO2. At passage 6, eMSC were incubated with or without A83-01 for 7 days, then analysed for MSC properties. A83-01 dose dependently promoted SUSD2+ eMSC proliferation and blocked apoptosis via the SMAD 2/3 pathway. Fewer A83-01 treated cells were autofluorescent or stained with β-galactosidase, indicating reduced senescence. A83-01-treated cells had higher cloning efficiency, differentiated into mesodermal lineages and expressed MSC phenotypic markers. These data suggest that A83-01 maintains SUSD2+ eMSC stemness, promoting proliferation by blocking senescence and apoptosis in late passage cultures through binding to TGF-β receptors. Small molecules such as A83-01 may enable the expansion of undifferentiated MSC for use in tissue engineering and cell-based therapies. PMID:26461813

  6. Inhibition of Transforming Growth Factor-β Receptor signaling promotes culture expansion of undifferentiated human Endometrial Mesenchymal Stem/stromal Cells.

    PubMed

    Gurung, Shanti; Werkmeister, Jerome A; Gargett, Caroline E

    2015-01-01

    Human endometrial MSC (eMSC) are a novel source of MSC easily harvested from the highly regenerative uterine lining. We have developed protocols for eMSC isolation from single cell suspensions using magnetic bead-sorting using a perivascular marker antibody to SUSD2 and culture expansion in serum free medium (SFM). Similar to other MSC, eMSC spontaneously differentiate into fibroblasts during culture expansion decreasing their purity and efficacy. The aim of this study was to determine if A83-01, a TGF-β receptor inhibitor prevents eMSC differentiation in culture. SUSD2(+) eMSC were cultured in SFM with bFGF/EGF in 5% O2/5% CO2. At passage 6, eMSC were incubated with or without A83-01 for 7 days, then analysed for MSC properties. A83-01 dose dependently promoted SUSD2(+) eMSC proliferation and blocked apoptosis via the SMAD 2/3 pathway. Fewer A83-01 treated cells were autofluorescent or stained with β-galactosidase, indicating reduced senescence. A83-01-treated cells had higher cloning efficiency, differentiated into mesodermal lineages and expressed MSC phenotypic markers. These data suggest that A83-01 maintains SUSD2(+) eMSC stemness, promoting proliferation by blocking senescence and apoptosis in late passage cultures through binding to TGF-β receptors. Small molecules such as A83-01 may enable the expansion of undifferentiated MSC for use in tissue engineering and cell-based therapies. PMID:26461813

  7. Gab2-Mediated Signaling Promotes Melanoma Metastasis

    PubMed Central

    Horst, Basil; Gruvberger-Saal, Sofia K.; Hopkins, Benjamin D.; Bordone, Lindsey; Yang, Ying; Chernoff, Karen A.; Uzoma, Ijeoma; Schwipper, Volker; Liebau, Jutta; Nowak, Norma J.; Brunner, Georg; Owens, David; Rimm, David L.; Parsons, Ramon; Celebi, Julide Tok

    2009-01-01

    Metastatic melanoma is a disease with a poor prognosis that currently lacks effective treatments. Critical biological features of metastasis include acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma pathogenesis, a genome-wide search using bacterial artificial chromosome array comparative genomic hybridization and single nucleotide polymorphism arrays in a series of 64 metastatic melanoma samples and 20 melanoma cell lines identified increased copy numbers of Gab2 located on 11q14.1. Gab2 is an adaptor protein that potentiates the activation of the Ras-Erk and PI3K-Akt pathways and has recently been implicated in human cancer; however, its role in melanoma has not been explored. In this study, we found that Gab2 was either amplified (∼11%) and/or overexpressed (∼50%) in melanoma. Gab2 protein expression correlated with clinical melanoma progression, and higher levels of expression were seen in metastatic melanomas compared with primary melanoma and melanocytic nevi. We found that overexpression of Gab2 potentiates, whereas silencing of Gab2 reduces, migration and invasion of melanoma cells. Gab2 mediated the hyperactivation of Akt signaling in the absence of growth factors, whereas inhibition of the PI3K-Akt pathway decreased Gab2-mediated tumor cell migration and invasive potential. Gab2 overexpression resulted in enhanced tumor growth and metastatic potential in vivo. These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis. PMID:19342374

  8. Mapping growth-factor-modulated Akt signaling dynamics.

    PubMed

    Gross, Sean M; Rotwein, Peter

    2016-05-15

    Growth factors alter cellular behavior through shared signaling cascades, raising the question of how specificity is achieved. Here, we have determined how growth factor actions are encoded into Akt signaling dynamics by real-time tracking of a fluorescent sensor. In individual cells, Akt activity was encoded in an analog pattern, with similar latencies (∼2 min) and half-maximal peak response times (range of 5-8 min). Yet, different growth factors promoted dose-dependent and heterogeneous changes in signaling dynamics. Insulin treatment caused sustained Akt activity, whereas EGF or PDGF-AA promoted transient signaling; PDGF-BB produced sustained responses at higher concentrations, but short-term effects at low doses, actions that were independent of the PDGF-α receptor. Transient responses to EGF were caused by negative feedback at the receptor level, as a second treatment yielded minimal responses, whereas parallel exposure to IGF-I caused full Akt activation. Small-molecule inhibitors reduced PDGF-BB signaling to transient responses, but only decreased the magnitude of IGF-I actions. Our observations reveal distinctions among growth factors that use shared components, and allow us to capture the consequences of receptor-specific regulatory mechanisms on Akt signaling. PMID:27044757

  9. Complementarity among plant growth promoting traits in rhizospheric bacterial communities promotes plant growth

    PubMed Central

    Singh, Mangal; Awasthi, Ashutosh; Soni, Sumit K.; Singh, Rakshapal; Verma, Rajesh K.; Kalra, Alok

    2015-01-01

    An assessment of roles of rhizospheric microbial diversity in plant growth is helpful in understanding plant-microbe interactions. Using random combinations of rhizospheric bacterial species at different richness levels, we analysed the contribution of species richness, compositions, interactions and identity on soil microbial respiration and plant biomass. We showed that bacterial inoculation in plant rhizosphere enhanced microbial respiration and plant biomass with complementary relationships among bacterial species. Plant growth was found to increase linearly with inoculation of rhizospheric bacterial communities with increasing levels of species or plant growth promoting trait diversity. However, inoculation of diverse bacterial communities having single plant growth promoting trait, i.e., nitrogen fixation could not enhance plant growth over inoculation of single bacteria. Our results indicate that bacterial diversity in rhizosphere affect ecosystem functioning through complementary relationship among plant growth promoting traits and may play significant roles in delivering microbial services to plants. PMID:26503744

  10. Insulin signaling regulates neurite growth during metamorphic neuronal remodeling

    PubMed Central

    Gu, Tingting; Zhao, Tao; Hewes, Randall S.

    2014-01-01

    Summary Although the growth capacity of mature neurons is often limited, some neurons can shift through largely unknown mechanisms from stable maintenance growth to dynamic, organizational growth (e.g. to repair injury, or during development transitions). During insect metamorphosis, many terminally differentiated larval neurons undergo extensive remodeling, involving elimination of larval neurites and outgrowth and elaboration of adult-specific projections. Here, we show in the fruit fly, Drosophila melanogaster (Meigen), that a metamorphosis-specific increase in insulin signaling promotes neuronal growth and axon branching after prolonged stability during the larval stages. FOXO, a negative effector in the insulin signaling pathway, blocked metamorphic growth of peptidergic neurons that secrete the neuropeptides CCAP and bursicon. RNA interference and CCAP/bursicon cell-targeted expression of dominant-negative constructs for other components of the insulin signaling pathway (InR, Pi3K92E, Akt1, S6K) also partially suppressed the growth of the CCAP/bursicon neuron somata and neurite arbor. In contrast, expression of wild-type or constitutively active forms of InR, Pi3K92E, Akt1, Rheb, and TOR, as well as RNA interference for negative regulators of insulin signaling (PTEN, FOXO), stimulated overgrowth. Interestingly, InR displayed little effect on larval CCAP/bursicon neuron growth, in contrast to its strong effects during metamorphosis. Manipulations of insulin signaling in many other peptidergic neurons revealed generalized growth stimulation during metamorphosis, but not during larval development. These findings reveal a fundamental shift in growth control mechanisms when mature, differentiated neurons enter a new phase of organizational growth. Moreover, they highlight strong evolutionarily conservation of insulin signaling in neuronal growth regulation. PMID:24357229

  11. PtdIns(3,4,5)P3-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) Activity Promotes Breast Cancer Cell Proliferation and Tumor Growth via Activation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Signaling.

    PubMed

    Liu, Heng-Jia; Ooms, Lisa M; Srijakotre, Nuthasuda; Man, Joey; Vieusseux, Jessica; Waters, JoAnne E; Feng, Yue; Bailey, Charles G; Rasko, John E J; Price, John T; Mitchell, Christina A

    2016-08-12

    PtdIns(3,4,5)P3-dependent Rac exchanger 1 (PREX1) is a Rac-guanine nucleotide exchange factor (GEF) overexpressed in a significant proportion of human breast cancers that integrates signals from upstream ErbB2/3 and CXCR4 membrane surface receptors. However, the PREX1 domains that facilitate its oncogenic activity and downstream signaling are not completely understood. We identify that ERK1/2 MAPK acts downstream of PREX1 and contributes to PREX1-mediated anchorage-independent cell growth. PREX1 overexpression increased but its shRNA knockdown decreased ERK1/2 phosphorylation in response to EGF/IGF-1 stimulation, resulting in induction of the cell cycle regulators cyclin D1 and p21(WAF1/CIP1) PREX1-mediated ERK1/2 phosphorylation, anchorage-independent cell growth, and cell migration were suppressed by inhibition of MEK1/2/ERK1/2 signaling. PREX1 overexpression reduced staurosporine-induced apoptosis whereas its shRNA knockdown promoted apoptosis in response to staurosporine or the anti-estrogen drug tamoxifen. Expression of wild-type but not GEF-inactive PREX1 increased anchorage-independent cell growth. In addition, mouse xenograft studies revealed that expression of wild-type but not GEF-dead PREX1 resulted in the formation of larger tumors that displayed increased phosphorylation of ERK1/2 but not AKT. The impaired anchorage-independent cell growth, apoptosis, and ERK1/2 signaling observed in stable PREX1 knockdown cells was restored by expression of wild-type but not GEF-dead-PREX1. Therefore, PREX1-Rac-GEF activity is critical for PREX1-dependent anchorage-independent cell growth and xenograft tumor growth and may represent a possible therapeutic target for breast cancers that exhibit PREX1 overexpression. PMID:27358402

  12. Plant growth-promoting rhizobacteria and root system functioning

    PubMed Central

    Vacheron, Jordan; Desbrosses, Guilhem; Bouffaud, Marie-Lara; Touraine, Bruno; Moënne-Loccoz, Yvan; Muller, Daniel; Legendre, Laurent; Wisniewski-Dyé, Florence; Prigent-Combaret, Claire

    2013-01-01

    The rhizosphere supports the development and activity of a huge and diversified microbial community, including microorganisms capable to promote plant growth. Among the latter, plant growth-promoting rhizobacteria (PGPR) colonize roots of monocots and dicots, and enhance plant growth by direct and indirect mechanisms. Modification of root system architecture by PGPR implicates the production of phytohormones and other signals that lead, mostly, to enhanced lateral root branching and development of root hairs. PGPR also modify root functioning, improve plant nutrition and influence the physiology of the whole plant. Recent results provided first clues as to how PGPR signals could trigger these plant responses. Whether local and/or systemic, the plant molecular pathways involved remain often unknown. From an ecological point of view, it emerged that PGPR form coherent functional groups, whose rhizosphere ecology is influenced by a myriad of abiotic and biotic factors in natural and agricultural soils, and these factors can in turn modulate PGPR effects on roots. In this paper, we address novel knowledge and gaps on PGPR modes of action and signals, and highlight recent progress on the links between plant morphological and physiological effects induced by PGPR. We also show the importance of taking into account the size, diversity, and gene expression patterns of PGPR assemblages in the rhizosphere to better understand their impact on plant growth and functioning. Integrating mechanistic and ecological knowledge on PGPR populations in soil will be a prerequisite to develop novel management strategies for sustainable agriculture. PMID:24062756

  13. Promotion of Bone Morphogenetic Protein Signaling by Tetraspanins and Glycosphingolipids

    PubMed Central

    Szymczak, Lindsey C.; Aydin, Taner; Yun, Sijung; Constas, Katharine; Schaeffer, Arielle; Ranjan, Sinthu; Kubba, Saad; Alam, Emad; McMahon, Devin E.; He, Jingpeng; Shwartz, Neta; Tian, Chenxi; Plavskin, Yevgeniy; Lindy, Amanda; Dad, Nimra Amir; Sheth, Sunny; Amin, Nirav M.; Zimmerman, Stephanie; Liu, Dennis; Schwarz, Erich M.; Smith, Harold; Krause, Michael W.; Liu, Jun

    2015-01-01

    Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like “Sma/Mab” signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development. PMID:25978409

  14. Plant growth promotion and Penicillium citrinum

    PubMed Central

    Khan, Sumera Afzal; Hamayun, Muhammad; Yoon, Hyeokjun; Kim, Ho-Youn; Suh, Seok-Jong; Hwang, Seon-Kap; Kim, Jong-Myeong; Lee, In-Jung; Choo, Yeon-Sik; Yoon, Ung-Han; Kong, Won-Sik; Lee, Byung-Moo; Kim, Jong-Guk

    2008-01-01

    Background Endophytic fungi are known plant symbionts. They produce a variety of beneficial metabolites for plant growth and survival, as well as defend their hosts from attack of certain pathogens. Coastal dunes are nutrient deficient and offer harsh, saline environment for the existing flora and fauna. Endophytic fungi may play an important role in plant survival by enhancing nutrient uptake and producing growth-promoting metabolites such as gibberellins and auxins. We screened roots of Ixeris repenes (L.) A. Gray, a common dune plant, for the isolation of gibberellin secreting endophytic fungi. Results We isolated 15 endophytic fungi from the roots of Ixeris repenes and screened them for growth promoting secondary metabolites. The fungal isolate IR-3-3 gave maximum plant growth when applied to waito-c rice and Atriplex gemelinii seedlings. Analysis of the culture filtrate of IR-3-3 showed the presence of physiologically active gibberellins, GA1, GA3, GA4 and GA7 (1.95 ng/ml, 3.83 ng/ml, 6.03 ng/ml and 2.35 ng/ml, respectively) along with other physiologically inactive GA5, GA9, GA12, GA15, GA19, GA20 and, GA24. The plant growth promotion and gibberellin producing capacity of IR-3-3 was much higher than the wild type Gibberella fujikuroi, which was taken as control during present study. GA5, a precursor of bioactive GA3 was reported for the first time in fungi. The fungal isolate IR-3-3 was identified as a new strain of Penicillium citrinum (named as P. citrinum KACC43900) through phylogenetic analysis of 18S rDNA sequence. Conclusion Isolation of new strain of Penicillium citrinum from the sand dune flora is interesting as information on the presence of Pencillium species in coastal sand dunes is limited. The plant growth promoting ability of this fungal strain may help in conservation and revegetation of the rapidly eroding sand dune flora. Penicillium citrinum is already known for producing mycotoxin citrinin and cellulose digesting enzymes like cellulase and

  15. RGS5 promotes arterial growth during arteriogenesis

    PubMed Central

    Arnold, Caroline; Feldner, Anja; Pfisterer, Larissa; Hödebeck, Maren; Troidl, Kerstin; Genové, Guillem; Wieland, Thomas; Hecker, Markus; Korff, Thomas

    2014-01-01

    Arteriogenesis—the growth of collateral arterioles—partially compensates for the progressive occlusion of large conductance arteries as it may occur as a consequence of coronary, cerebral or peripheral artery disease. Despite being clinically highly relevant, mechanisms driving this process remain elusive. In this context, our study revealed that abundance of regulator of G-protein signalling 5 (RGS5) is increased in vascular smooth muscle cells (SMCs) of remodelling collateral arterioles. RGS5 terminates G-protein-coupled signalling cascades which control contractile responses of SMCs. Consequently, overexpression of RGS5 blunted Gαq/11-mediated mobilization of intracellular calcium, thereby facilitating Gα12/13-mediated RhoA signalling which is crucial for arteriogenesis. Knockdown of RGS5 evoked opposite effects and thus strongly impaired collateral growth as evidenced by a blockade of RhoA activation, SMC proliferation and the inability of these cells to acquire an activated phenotype in RGS5-deficient mice after the onset of arteriogenesis. Collectively, these findings establish RGS5 as a novel determinant of arteriogenesis which shifts G-protein signalling from Gαq/11-mediated calcium-dependent contraction towards Gα12/13-mediated Rho kinase-dependent SMC activation. Subject Categories Vascular Biology & Angiogenesis PMID:24972930

  16. Leptin-Induced JAK/STAT Signaling and Cancer Growth.

    PubMed

    Mullen, McKay; Gonzalez-Perez, Ruben Rene

    2016-01-01

    Growth factor and cytokine signaling can influence the development of several cancer types. One of the key players in the development of cancer is the Janus kinas (JAK) signal transducer of activators of transcription (STAT) signaling pathway. The majority of growth factors and cytokine interactions with their membrane-bound receptors trigger JAK-STAT activation. The influential relationship between obesity and cancer is a fact. However, there is a complex sequence of events contributing to the regulation of this mechanism to promote tumor growth, yet to be fully elucidated. The JAK-STAT pathway is influenced by obesity-associated changes that have been shown to impact cancer growth and progression. This intricate process is highly regulated by a vast array of adipokines and cytokines that exert their pleiotropic effects on cancer cells to enhance metastasis to distant target sites. Leptin is a cytokine, or more precise, an adipokine secreted mainly by adipose tissue that requires JAK-STAT activation to exert its biological functions. Leptin is the central regulator of energy balance and appetite. Leptin binding to its receptor OB-R in turn activates JAK-STAT, which induces proliferation, angiogenesis, and anti-apoptotic events in normal cells and malignant cells expressing the receptor. Leptin also induces crosstalk with Notch and IL-1 (NILCO), which involves other angiogenic factors promoting tumor growth. Therefore, the existence of multiple novel classes of therapeutics that target the JAK/STAT pathway has significant clinical implications. Then, the identification of the signaling networks and factors that regulate the obesity-cancer link to which potential pharmacologic interventions can be implemented to inhibit tumor growth and metastasis. In this review, we will discuss the specific relationship between leptin-JAK-STAT signaling and cancer. PMID:27472371

  17. Y-P30 promotes axonal growth by stabilizing growth cones.

    PubMed

    Neumann, Janine R; Dash-Wagh, Suvarna; Jüngling, Kay; Tsai, Teresa; Meschkat, Martin; Räk, Andrea; Schönfelder, Sabine; Riedel, Christian; Hamad, Mohammad I K; Wiese, Stefan; Pape, Hans-Christian; Gottmann, Kurt; Kreutz, Michael R; Wahle, Petra

    2015-07-01

    The 30-amino acid peptide Y-P30, generated from the N-terminus of the human dermcidin precursor protein, has been found to promote neuronal survival, cell migration and neurite outgrowth by enhancing the interaction of pleiotrophin and syndecan-3. We now show that Y-P30 activates Src kinase and extracellular signal-regulated kinase (ERK). Y-P30 promotes axonal growth of mouse embryonic stem cell-derived neurons, embryonic mouse spinal cord motoneurons, perinatal rat retinal neurons, and rat cortical neurons. Y-P30-mediated axon growth was dependent on heparan sulfate chains. Y-P30 decreased the proportion of collapsing/degenerating growth cones of cortical axons in an Src and ERK-dependent manner. Y-P30 increased for 90 min in axonal growth cones the level of Tyr418-phosphorylated Src kinase and the amount of F-actin, and transiently the level of Tyr-phosphorylated ERK. Levels of total Src kinase, actin, GAP-43, cortactin and the glutamate receptor subunit GluN2B were not altered. When exposed to semaphorin-3a, Y-P30 protected a significant fraction of growth cones of cortical neurons from collapse. These results suggest that Y-P30 promotes axonal growth via Src- and ERK-dependent mechanisms which stabilize growth cones and confer resistance to collapsing factors. PMID:24728870

  18. EGF signaling patterns the feather array by promoting the interbud fate.

    PubMed

    Atit, Radhika; Conlon, Ronald A; Niswander, Lee

    2003-02-01

    Feather buds form sequentially in a hexagonal array. Bone morphogenetic protein (BMP) signaling from the feather bud inhibits bud formation in the adjacent interbud tissue, but whether interbud fate and patterning is actively promoted by BMP or other factors is unclear. We show that epidermal growth factor (EGF) signaling acts positively to establish interbud identity. EGF and the active EGF receptor (EGFR) are expressed in the interbud regions. Exogenous EGF stimulates epidermal proliferation and expands interbud gene expression, with a concurrent loss of feather bud gene expression and morphology. Conversely, EGFR inhibitors result in the loss of interbud fate and increased acquisition of feather bud fate. EGF signaling acts directly on the epidermis and is independent of BMP signaling. The timing of competence to interpret interbud-promoting signals occurs at an earlier developmental stage than previously anticipated. These data demonstrate that EGFR signaling actively promotes interbud identity. PMID:12586066

  19. Growth Factor Mediated Signaling in Pancreatic Pathogenesis

    PubMed Central

    Nandy, Debashis; Mukhopadhyay, Debabrata

    2011-01-01

    Functionally, the pancreas consists of two types of tissues: exocrine and endocrine. Exocrine pancreatic disorders mainly involve acute and chronic pancreatitis. Acute pancreatitis typically is benign, while chronic pancreatitis is considered a risk factor for developing pancreatic cancer. Pancreatic carcinoma is the fourth leading cause of cancer related deaths worldwide. Most pancreatic cancers develop in the exocrine tissues. Endocrine pancreatic tumors are more uncommon, and typically are less aggressive than exocrine tumors. However, the endocrine pancreatic disorder, diabetes, is a dominant cause of morbidity and mortality. Importantly, different growth factors and their receptors play critical roles in pancreatic pathogenesis. Hence, an improved understanding of how various growth factors affect pancreatitis and pancreatic carcinoma is necessary to determine appropriate treatment. This chapter describes the role of different growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and transforming growth factor (TGF) in various pancreatic pathophysiologies. Finally, the crosstalk between different growth factor axes and their respective signaling mechanisms, which are involved in pancreatitis and pancreatic carcinoma, are also discussed. PMID:24212642

  20. Soliton growth-signal transduction in topologically quantized T cells

    NASA Astrophysics Data System (ADS)

    Matsson, Leif

    1993-09-01

    A model for growth-signal transduction of the T cell and its growth factor, interleukin-2, is presented. It is obtained as a generalization of the usual rate equation and is founded on the observation that a definite number of receptor occupations must take place in order to promote transition to the S phase and subsequent DNA replication. The generalized rate equation is identified as the equation of motion of a Lagrangian field theory of Ginzburg-Landau (Goldstone) type. However it is not an ad hoc model but is a microscopic theory of the interaction of interleukin-2 and its receptor. The topological quantum number of the model is related to the observed definite number of receptor occupations required to elicit growth-signal transduction. Individual receptor quanta, up to this limit, are subjected to a type of Bose condensation. This collective excitation constitutes the growth signal in the form of a topological kink soliton which is then launched by the next potential receptor occupation that makes the interaction repulsive. The model provides a possible long-absent explanation of the triggering mechanism for growth-signal transduction by means of the ambivalent interaction, which switches sign after a definite number of receptor occupations. Moreover, it offers an explanation of how Nature screens out fractional signals in the growth-signal-transduction process of T cells. Although the model is derived for assumed point-like cells and certain other restrictions, the obtained dose-response curves are in striking agreement with proliferation data from studies of both the leukemic T cell line MLA-144 from gibbon ape and normal human T cells in, and without, the presence of monoclonal anti-Tac antibodies.

  1. The Fibroblast Growth Factor signaling pathway

    PubMed Central

    Ornitz, David M; Itoh, Nobuyuki

    2015-01-01

    The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. © 2015 Wiley Periodicals, Inc. PMID:25772309

  2. Epidermal growth factor signaling in transformed cells

    PubMed Central

    Lindsey, Stephan; Langhans, Sigrid A.

    2016-01-01

    Members of the epidermal growth factor receptor (EGFR/ErbB) family play a critical role in normal cell growth and development. However, many ErbB family members, especially EGFR, are aberrantly expressed or deregulated in tumors and are thought to play crucial roles in cancer development and metastatic progression. In this chapter, we provide an overview of key mechanisms contributing to aberrant EGFR/ErbB signaling in transformed cells which results in many phenotypic changes associated with the earliest stages of tumor formation, including several hallmarks of epithelial-to-mesenchymal transition (EMT). These changes often occur through interaction with other major signaling pathways important to tumor progression resulting in a multitude of transcriptional changes that ultimately impact cell morphology, proliferation and adhesion, all of which are crucial for tumor progression. The resulting mesh of signaling networks will need to be taken into account as new regimens are designed for targeting EGFR for therapeutic intervention. As new insights into the molecular mechanisms of the cross-talk of EGFR signaling with other signaling pathways and their role in therapeutic resistance to anti-EGFR therapies are gained a continual reassessment of clinical therapeutic regimes and strategies will be required. Understanding the consequences and complexity of EGF signaling and how it relates to tumor progression is critical for the development of clinical compounds and establishing clinical protocols for the treatment of cancer. PMID:25619714

  3. P311 promotes renal fibrosis via TGFβ1/Smad signaling

    PubMed Central

    Yao, Zhihui; Yang, Sisi; He, Weifeng; Li, Lian; Xu, Rui; Zhang, Xiaorong; Li, Haisheng; Zhan, Rixing; Sun, Wei; Tan, Jianglin; Zhou, Junyi; Luo, Gaoxing; Wu, Jun

    2015-01-01

    P311, a gene that was identified in 1993, has been found to have diverse biological functions in processes such as cell proliferation, migration and differentiation. However, its role in fibrosis is unknown. We previously observed that P311 is highly expressed in skin hypertrophic scars. In this study, P311 over-expression was detected in a subset of tubular epithelial cells in clinical biopsy specimens of renal fibrosis; this over-expression, was found concurrent with α-smooth muscle actin (α-SMA) and transforming growth factor beta1 (TGFβ1) expression. Subsequently, these results were verified in a mouse experimental renal fibrosis model induced by unilateral ureteral obstruction. The interstitial deposition of collagen, α-SMA and TGF-β1 expression, and macrophage infiltration were dramatically decreased when P311 was knocked out. Moreover, TGFβ/Smad signaling had a critical effect on the promotion of renal fibrosis by P311. In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFβ1/Smad signaling, which could be a novel target for the management of renal fibrosis. PMID:26616407

  4. The role of microbial signals in plant growth and development

    PubMed Central

    Ortíz-Castro, Randy; Contreras-Cornejo, Hexon Angel; Macías-Rodríguez, Lourdes

    2009-01-01

    Plant growth and development involves a tight coordination of the spatial and temporal organization of cell division, cell expansion and cell differentiation. Orchestration of these events requires the exchange of signaling molecules between the root and shoot, which can be affected by both biotic and abiotic factors. The interactions that occur between plants and their associated microorganisms have long been of interest, as knowledge of these processes could lead to the development of novel agricultural applications. Plants produce a wide range of organic compounds including sugars, organic acids and vitamins, which can be used as nutrients or signals by microbial populations. On the other hand, microorganisms release phytohormones, small molecules or volatile compounds, which may act directly or indirectly to activate plant immunity or regulate plant growth and morphogenesis. In this review, we focus on recent developments in the identification of signals from free-living bacteria and fungi that interact with plants in a beneficial way. Evidence has accumulated indicating that classic plant signals such as auxins and cytokinins can be produced by microorganisms to efficiently colonize the root and modulate root system architecture. Other classes of signals, including N-acyl-L-homoserine lactones, which are used by bacteria for cell-to-cell communication, can be perceived by plants to modulate gene expression, metabolism and growth. Finally, we discuss the role played by volatile organic compounds released by certain plant growth-promoting rhizobacteria in plant immunity and developmental processes. The picture that emerges is one in which plants and microbes communicate themselves through transkingdom signaling systems involving classic and novel signals. PMID:19820333

  5. Decreased ferroportin promotes myeloma cell growth and osteoclast differentiation.

    PubMed

    Gu, Zhimin; Wang, He; Xia, Jiliang; Yang, Ye; Jin, Zhendong; Xu, Hongwei; Shi, Jumei; De Domenico, Ivana; Tricot, Guido; Zhan, Fenghuang

    2015-06-01

    Iron homeostasis is disrupted in multiple myeloma, a difficult-to-cure plasma cell malignancy with lytic bone lesions. Here, we systematically analyzed iron gene expression signature and demonstrated that mRNA expression of iron exporter ferroportin (FPN1) is significantly downregulated in myeloma cells and correlates negatively with clinic outcome. Restoring expression of FPN1 reduces intracellular liable iron pool, inhibits STAT3-MCL-1 signaling, and suppresses myeloma cells growth. Furthermore, we demonstrated that mRNA of FPN1 is also downregulated at the initial stages of osteoclast differentiation and suppresses myeloma cell-induced osteoclast differentiation through regulating iron regulator TFRC, NF-κB, and JNK pathways. Altogether, we demonstrated that downregulation of FPN1 plays critical roles in promoting myeloma cell growth and bone resorption in multiple myeloma. PMID:25855377

  6. Death Receptor 5 Signaling Promotes Hepatocyte Lipoapoptosis*

    PubMed Central

    Cazanave, Sophie C.; Mott, Justin L.; Bronk, Steven F.; Werneburg, Nathan W.; Fingas, Christian D.; Meng, X. Wei; Finnberg, Niklas; El-Deiry, Wafik S.; Kaufmann, Scott H.; Gores, Gregory J.

    2011-01-01

    Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR−/−) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligand-independent cytotoxic signaling by this death receptor. PMID:21941003

  7. Mitochondrial Stress Signaling Promotes Cellular Adaptations

    PubMed Central

    2014-01-01

    Mitochondrial dysfunction has been implicated in the aetiology of many complex diseases, as well as the ageing process. Much of the research on mitochondrial dysfunction has focused on how mitochondrial damage may potentiate pathological phenotypes. The purpose of this review is to draw attention to the less well-studied mechanisms by which the cell adapts to mitochondrial perturbations. This involves communication of stress to the cell and successful induction of quality control responses, which include mitophagy, unfolded protein response, upregulation of antioxidant and DNA repair enzymes, morphological changes, and if all else fails apoptosis. The mitochondrion is an inherently stressful environment and we speculate that dysregulation of stress signaling or an inability to switch on these adaptations during times of mitochondrial stress may underpin mitochondrial dysfunction and hence amount to pathological states over time. PMID:24587804

  8. Ethylene Promotes Elongation Growth and Auxin Promotes Radial Growth in Ranunculus sceleratus Petioles 1

    PubMed Central

    Smulders, Marinus J. M.; Horton, Roger F.

    1991-01-01

    Submergence induces elongation in the petioles of Ranunculus sceleratus L., after a rise in endogenous ethylene levels in the tissue. Petioles of isolated leaves also elongate 100% in 24 hours when treated with ethylene gas, without a change in the radius. Application of silver thiosulfate, aminoethoxyvinylglycine (AVG), abscisic acid (ABA), or methyl jasmonate inhibits this elongation response. Gibberellic acid treatment promotes ethylene-induced elongation, without an effect on the radius. Indoelastic acid (IAA) induces radial growth in the petioles, irrespective of the presence or absence of added ethylene. High concentrations of IAA will also induce elongation growth, but this is largely due to auxin-induced ethylene synthesis; treatment with silver thiosulfate, AVG, ABA, or methyl jasmonate inhibit this auxin-promoted elongation growth. However, the radial growth induced by IAA is not affected by gibberellic acid, and not specifically inhibited by ABA, methyl jasmonate, silver thiosulfate, or AVG. These results support the idea that petiole cell elongation during “accommodation growth” can be separated from radial expansion. The radial expansion may well be regulated by IAA. However, effects of high levels of IAA are probably anomalous, since they do not mimic normal developmental patterns. PMID:16668257

  9. A natural plant growth promoter calliterpenone from a plant Callicarpa macrophylla Vahl improves the plant growth promoting effects of plant growth promoting rhizobacteria (PGPRs).

    PubMed

    Maji, Deepamala; Barnawal, Deepti; Gupta, Aakansha; King, Shikha; Singh, A K; Kalra, A

    2013-05-01

    Experiments were conducted to evaluate the efficacy of calliterpenone, a natural plant growth promoter from a shrub Callicarpa macrophylla Vahl., in enhancing the growth and yield promoting effects of plant growth promoting rhizobacteria (PGPRs), in menthol mint (Mentha arvensis L).This study is based on our previous results indicating the microbial growth promotion by calliterpenone and assumption that application of calliterpenone along with PGPRs will improve the population of PGPRs resulting in higher impacts on plant growth and yield. Of the 15 PGPRs (identified as potent ones in our laboratory), 25 μl of 0.01 mM calliterpenone (8.0 μg/100 ml) was found to be useful in improving the population of nine PGPRs in culture media. The five selected strains of PGPRs exhibiting synergy with calliterpenone in enhancing growth of maize compared to PGPR or calliterpenone alone were selected and tested on two cultivars (cvs. Kosi and Kushal) of M. arvensis. Of the five strains, Bacillus subtilis P-20 (16S rDNA sequence homologous to Accession No NR027552) and B. subtilis Daz-26 (16SrDNA sequence homologuos to Accession No GU998816) were found to be highly effective in improving the herb and essential oil yield in the cultivars Kushal and Kosi respectively when co-treated with calliterpenone. The results open up the possibilities of using a natural growth promoter along with PGPRs as a bio-agri input for sustainable and organic agriculture. PMID:23271460

  10. Hair Growth Promotion Activity and Its Mechanism of Polygonum multiflorum

    PubMed Central

    Li, Yunfei; Han, Mingnuan; Lin, Pei; He, Yanran; Yu, Jie; Zhao, Ronghua

    2015-01-01

    Polygonum multiflorum Radix (PMR) has long history in hair growth promotion and hair coloring in clinical applications. However, several crucial problems in its clinic usage and mechanisms are still unsolved or lack scientific evidences. In this research, C57BL/6J mice were used to investigate hair growth promotion activity and possible mechanism of PMR and Polygonum multiflorum Radix Preparata (PMRP). Hair growth promotion activities were investigated by hair length, hair covered skin ratio, the number of follicles, and hair color. Regulation effects of several cytokines involved in the hair growth procedure were tested, such as fibroblast growth factor (FGF-7), Sonic Hedgehog (SHH), β-catenin, insulin-like growth factor-1 (IGF-1), and hepatocyte growth factor (HGF). Oral PMR groups had higher hair covered skin ratio (100 ± 0.00%) than oral PMRP groups (48%~88%). However, topical usage of PMRP had about 90% hair covered skin ratio. Both oral administration of PMR and topically given PMRP showed hair growth promotion activities. PMR was considered to be more suitable for oral administration, while PMRP showed greater effects in external use. The hair growth promotion effect of oral PMR was most probably mediated by the expression of FGF-7, while topical PMRP promoted hair growth by the stimulation of SHH expression. PMID:26294926

  11. Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

    PubMed Central

    Chabu, Chiswili; Xu, Tian

    2014-01-01

    Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how oncogenic Ras exerts its effects. Furthermore, cancers with oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of oncogenic Ras in an in vivo Drosophila mosaic screen. We found that oncogenic Ras elevates exocytosis and promotes the export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses oncogenic Ras-mediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches. PMID:25411211

  12. Multitrait plant growth promoting (PGP) rhizobacterial isolates from Brassica juncea rhizosphere : Keratin degradation and growth promotion.

    PubMed

    Anwar, Mohmmad Shahbaz; Siddique, Mohammad Tahir; Verma, Amit; Rao, Yalaga Rama; Nailwal, Tapan; Ansari, Mohammad; Pande, Veena

    2014-01-01

    Plant growth promoting (PGP) rhizobacteria, a beneficial microbe colonizing plant roots, enhanced crop productivity and offers an attractive way to replace chemical fertilizers, pesticides, and supplements. The keratinous waste which comprises feathers, hairs, nails, skin and wool creates problem of solid waste management due to presence of highly recalcitrant keratin. The multi traits rhizobacteria effective to remove both keratine from the environment by producing keratinase enzyme and to eradicate the chemical fertilizer by providing different PGP activity is novel achievement. In the present study, the effective PM2 strain of PGPR was isolated from rhizospheric soil of mustard (Brassica juncea) field, Pantnagar and they were identified on the basis of different biochemical tests as belonging to Bacillus genera. Different plant growth promoting activity, feather degradation and keratinolytic activity was performed and found very effective toward all the parameters. Furthermore, the efficient strain PM2 was identified on the basis of 16s rRNA sequencing and confirmed as Bacillus cereus. The strain PM2 might be used efficiently for keratinous waste management and PGP activity. Therefore, the present study suggests that Bacillus cereus have multi traits activity which extremely useful for different PGP activity and biotechnological process involving keratin hydrolysis, feather biodegradation or in the leather industry. PMID:24778758

  13. Signaling in Pollen Tube Growth: Crosstalk, Feedback, and Missing Links

    PubMed Central

    Guan, Yuefeng

    2013-01-01

    Pollen tubes elongate rapidly at their tips through highly polarized cell growth known as tip growth. Tip growth requires intensive exocytosis at the tip, which is supported by a dynamic cytoskeleton and vesicle trafficking. Several signaling pathways have been demonstrated to coordinate pollen tube growth by regulating cellular activities such as actin dynamics, exocytosis, and endocytosis. These signaling pathways crosstalk to form a signaling network that coordinates the cellular processes required for tip growth. The homeostasis of key signaling molecules is critical for the proper elongation of the pollen tube tip, and is commonly fine-tuned by positive and negative regulations. In addition to the major signaling pathways, emerging evidence implies the roles of other signals in the regulation of pollen tube growth. Here we review and discuss how these signaling networks modulate the rapid growth of pollen tubes. PMID:23873928

  14. Intracellular autocrine VEGF signaling promotes EBDC cell proliferation, which can be inhibited by Apatinib.

    PubMed

    Peng, Sui; Zhang, Yanyan; Peng, Hong; Ke, Zunfu; Xu, Lixia; Su, Tianhong; Tsung, Allan; Tohme, Samer; Huang, Hai; Zhang, Qiuyang; Lencioni, Riccardo; Zeng, Zhirong; Peng, Baogang; Chen, Minhu; Kuang, Ming

    2016-04-10

    Tumor cells produce vascular endothelial growth factor (VEGF) which can interact with membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth. We aimed to investigate the role of extracellular/intracellular autocrine VEGF signaling and Apatinib, a highly selective VEGFR2 inhibitor, in extrahepatic bile duct cancer (EBDC). We found conditioned medium or recombinant human VEGF treatment promoted EBDC cell proliferation through a phospholipase C-γ1-dependent pathway. This pro-proliferative effect was diminished by VEGF, VEGFR1 or VEGFR2 neutralizing antibodies, but more significantly suppressed by intracellular VEGFR inhibitor. The rhVEGF induced intracellular VEGF signaling by promoting nuclear accumulation of pVEGFR1/2 and enhancing VEGF promoter activity, mRNA and protein expression. Internal VEGFR2 inhibitor Apatinib significantly inhibited intracellular VEGF signaling, suppressed cell proliferation in vitro and delayed xenograft tumor growth in vivo, while anti-VEGF antibody Bevacizumab showed no effect. Clinically, overexpression of pVEGFR1 and pVEGFR2 was significantly correlated with poorer overall survival (P = .007 and P = .020, respectively). In conclusion, the intracellular autocrine VEGF loop plays a predominant role in VEGF-induced cell proliferation. Apatinib is an effective intracellular VEGF pathway blocker that presents a great therapeutic potential in EBDC. PMID:26805764

  15. Plant growth-promoting oligosaccharides produced from tomato waste.

    PubMed

    Suzuki, Toshisada; Tomita-Yokotani, Kaori; Tsubura, Hirokazu; Yoshida, Shigeki; Kusakabe, Isao; Yamada, Kosumi; Miki, Yoichi; Hasegawa, Koji

    2002-01-01

    Tomato juice waste was hydrolyzed with acid. Tomato juice waste (500 g; wet weight) was heated with 0.5 N HCl (2.5 l) at 70 degrees C for 4 h. After neutralization, the growth-promoting extracts (300 g; dry weight) in the plants were produced from the tomato waste. The acid extract significantly promoted the growth of cockscomb (Celosia argentea L.) and tomato (Lycopersicon esculentum L.) seedlings. We have recognized potent plant growth-promoting substances in the acid extract from tomato waste. The most effective components in the active fraction were almost all oligogalacturonic acids (DP 6-12). This paper is the first report that plant growth-promoting oligosaccharides can be directly produced from tomato juice waste. It is possible that the substances from the tomato waste can become useful plant growth regulators in the agriculture field in the future. PMID:11762911

  16. Lack of Collagen VI Promotes Wound-Induced Hair Growth.

    PubMed

    Chen, Peiwen; Cescon, Matilde; Bonaldo, Paolo

    2015-10-01

    Collagen VI is an extracellular matrix molecule that is abundantly expressed in the skin. However, the role of collagen VI in hair follicle growth is unknown. Here, we show that collagen VI is strongly deposited in hair follicles, and is markedly upregulated by skin wounding. Lack of collagen VI in Col6a1(-/-) mice delays hair cycling and growth under physiological conditions, but promotes wound-induced hair regrowth without affecting skin regeneration. Conversely, addition of purified collagen VI rescues the abnormal wound-induced hair regrowth in Col6a1(-/-) mice. Mechanistic studies revealed that the increased wound-induced hair regrowth of Col6a1(-/-) mice is triggered by activation of the Wnt/β-catenin signaling pathway, and is abolished by inhibition of this pathway. These findings highlight the essential relationships between extracellular matrix (ECM) and hair follicle regeneration, and suggest that collagen VI could be a potential therapeutic target for hair loss and other skin-related diseases. PMID:25989472

  17. Promoter nucleosome dynamics regulated by signalling through the CTD code.

    PubMed

    Materne, Philippe; Anandhakumar, Jayamani; Migeot, Valerie; Soriano, Ignacio; Yague-Sanz, Carlo; Hidalgo, Elena; Mignion, Carole; Quintales, Luis; Antequera, Francisco; Hermand, Damien

    2015-01-01

    The phosphorylation of the RNA polymerase II C-terminal domain (CTD) plays a key role in delineating transcribed regions within chromatin by recruiting histone methylases and deacetylases. Using genome-wide nucleosome mapping, we show that CTD S2 phosphorylation controls nucleosome dynamics in the promoter of a subset of 324 genes, including the regulators of cell differentiation ste11 and metabolic adaptation inv1. Mechanistic studies on these genes indicate that during gene activation a local increase of phospho-S2 CTD nearby the promoter impairs the phospho-S5 CTD-dependent recruitment of Set1 and the subsequent recruitment of specific HDACs, which leads to nucleosome depletion and efficient transcription. The early increase of phospho-S2 results from the phosphorylation of the CTD S2 kinase Lsk1 by MAP kinase in response to cellular signalling. The artificial tethering of the Lsk1 kinase at the ste11 promoter is sufficient to activate transcription. Therefore, signalling through the CTD code regulates promoter nucleosomes dynamics. PMID:26098123

  18. Promoter nucleosome dynamics regulated by signalling through the CTD code

    PubMed Central

    Materne, Philippe; Anandhakumar, Jayamani; Migeot, Valerie; Soriano, Ignacio; Yague-Sanz, Carlo; Hidalgo, Elena; Mignion, Carole; Quintales, Luis; Antequera, Francisco; Hermand, Damien

    2015-01-01

    The phosphorylation of the RNA polymerase II C-terminal domain (CTD) plays a key role in delineating transcribed regions within chromatin by recruiting histone methylases and deacetylases. Using genome-wide nucleosome mapping, we show that CTD S2 phosphorylation controls nucleosome dynamics in the promoter of a subset of 324 genes, including the regulators of cell differentiation ste11 and metabolic adaptation inv1. Mechanistic studies on these genes indicate that during gene activation a local increase of phospho-S2 CTD nearby the promoter impairs the phospho-S5 CTD-dependent recruitment of Set1 and the subsequent recruitment of specific HDACs, which leads to nucleosome depletion and efficient transcription. The early increase of phospho-S2 results from the phosphorylation of the CTD S2 kinase Lsk1 by MAP kinase in response to cellular signalling. The artificial tethering of the Lsk1 kinase at the ste11 promoter is sufficient to activate transcription. Therefore, signalling through the CTD code regulates promoter nucleosomes dynamics. DOI: http://dx.doi.org/10.7554/eLife.09008.001 PMID:26098123

  19. Fibroblast Growth Factor Signaling in Metabolic Regulation

    PubMed Central

    Nies, Vera J. M.; Sancar, Gencer; Liu, Weilin; van Zutphen, Tim; Struik, Dicky; Yu, Ruth T.; Atkins, Annette R.; Evans, Ronald M.; Jonker, Johan W.; Downes, Michael Robert

    2016-01-01

    The prevalence of obesity is a growing health problem. Obesity is strongly associated with several comorbidities, such as non-alcoholic fatty liver disease, certain cancers, insulin resistance, and type 2 diabetes, which all reduce life expectancy and life quality. Several drugs have been put forward in order to treat these diseases, but many of them have detrimental side effects. The unexpected role of the family of fibroblast growth factors in the regulation of energy metabolism provides new approaches to the treatment of metabolic diseases and offers a valuable tool to gain more insight into metabolic regulation. The known beneficial effects of FGF19 and FGF21 on metabolism, together with recently discovered similar effects of FGF1 suggest that FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. To facilitate the development of new therapies with improved targeting and minimal side effects, a better understanding of the molecular mechanism of action of FGFs is needed. In this review, we will discuss what is currently known about the physiological roles of FGF signaling in tissues important for metabolic homeostasis. In addition, we will discuss current concepts regarding their pharmacological properties and effector tissues in the context of metabolic disease. Also, the recent progress in the development of FGF variants will be reviewed. Our goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease and to provide starting points for the development of FGF-based therapies against metabolic conditions. PMID:26834701

  20. dFoxO promotes Wingless signaling in Drosophila

    PubMed Central

    Zhang, Shiping; Guo, Xiaowei; Chen, Changyan; Chen, Yujun; Li, Jikai; Sun, Ying; Wu, Chenxi; Yang, Yang; Jiang, Cizhong; Li, Wenzhe; Xue, Lei

    2016-01-01

    The Wnt/β-catenin signaling is an evolutionarily conserved pathway that regulates a wide range of physiological functions, including embryogenesis, organ maintenance, cell proliferation and cell fate decision. Dysregulation of Wnt/β-catenin signaling has been implicated in various cancers, but its role in cell death has not yet been fully elucidated. Here we show that activation of Wg signaling induces cell death in Drosophila eyes and wings, which depends on dFoxO, a transcription factor known to be involved in cell death. In addition, dFoxO is required for ectopic and endogenous Wg signaling to regulate wing patterning. Moreover, dFoxO is necessary for activated Wg signaling-induced target genes expression. Furthermore, Arm is reciprocally required for dFoxO-induced cell death. Finally, dFoxO physically interacts with Arm both in vitro and in vivo. Thus, we have characterized a previously unknown role of dFoxO in promoting Wg signaling, and that a dFoxO-Arm complex is likely involved in their mutual functions, e.g. cell death. PMID:26936649

  1. Nodal signaling promotes a tumorigenic phenotype in human breast cancer.

    PubMed

    Kirsammer, Gina; Strizzi, Luigi; Margaryan, Naira V; Gilgur, Alina; Hyser, Matthew; Atkinson, Janis; Kirschmann, Dawn A; Seftor, Elisabeth A; Hendrix, Mary J C

    2014-12-01

    The Ras-ERK pathway is deregulated in approximately a third of human cancers, particularly those of epithelial origin. In aggressive, triple-negative, basal-like breast cancers, most tumors display increased MEK and ERK phosphorylation and exhibit a gene expression profile characteristic of Kras or EGFR mutant tumors; however, Ras family genetic mutations are uncommon in triple-negative breast cancer and EGFR mutations account for only a subset of these tumors. Therefore, the upstream events that activate MAPK signaling and promote tumor aggression in triple-negative breast cancers remain poorly defined. We have previously shown that a secreted TGF-β family signaling ligand, Nodal, is expressed in breast cancer in correlation with disease progression. Here we highlight key findings demonstrating that Nodal is required in aggressive human breast cancer cells to activate ERK signaling and downstream tumorigenic phenotypes both in vitro and in vivo. Experimental knockdown of Nodal signaling downregulates ERK activity, resulting in loss of c-myc, upregulation of p27, G1 cell cycle arrest, increased apoptosis and decreased tumorigenicity. The data suggest that ERK activation by Nodal signaling regulates c-myc and p27 proteins post-translationally and that this cascade is essential for aggressive breast tumor behavior in vivo. As the MAPK pathway is an important target for treating triple-negative breast cancers, upstream Nodal signaling may represent a promising target for breast cancer diagnosis and combined therapies aimed at blocking ERK pathway activation. PMID:25073112

  2. Nodal signaling promotes a tumorigenic phenotype in human breast cancer

    PubMed Central

    Kirsammer, Gina; Strizzi, Luigi; Margaryan, Naira V.; Gilgur, Alina; Hyser, Matthew; Atkinson, Janis; Kirschmann, Dawn A.; Seftor, Elisabeth A.; Hendrix, Mary J.C.

    2014-01-01

    The Ras-ERK pathway is deregulated in approximately a third of human cancers, particularly those of epithelial origin. In aggressive, triple-negative, basal-like breast cancers, most tumors display increased MEK and ERK phosphorylation and exhibit a gene expression profile characteristic of Kras or EGFR mutant tumors; however, Ras family genetic mutations are uncommon in triple-negative breast cancer and EGFR mutations account for only a subset of these tumors. Therefore, the upstream events that activate MAPK signaling and promote tumor aggression in triple-negative breast cancers remain poorly defined. We have previously shown that a secreted TGF-β family signaling ligand, Nodal, is expressed in breast cancer in correlation with disease progression. Here we highlight key findings demonstrating that Nodal is required in aggressive human breast cancer cells to activate ERK signaling and downstream tumorigenic phenotypes both in vitro and in vivo. Experimental knockdown of Nodal signaling downregulates ERK activity, resulting in loss of c-myc, upregulation of p27, G1 cell cycle arrest, increased apoptosis and decreased tumorigenicity. The data suggest that ERK activation by Nodal signaling regulates c-myc and p27 proteins post-translationally and that this cascade is essential for aggressive breast tumor behavior in vivo. As the MAPK pathway is an important target for treating triple-negative breast cancers, upstream Nodal signaling may represent a promising target for breast cancer diagnosis and combined therapies aimed at blocking ERK pathway activation. PMID:25073112

  3. Signal transduction by the growth hormone receptor

    SciTech Connect

    Waters, M.J.; Rowlinson, S.W.; Clarkson, R.W.

    1994-12-31

    It has been proposed that dimerization of identical receptor subunits by growth hormone (GH) is the mechanism of signal transduction across the cell membrane. We present here data with analogs of porcine GH (pGH), with GH receptors (GHR) mutated in the dimerization domain and with monoclonal antibodies to the GHR which indicate that dimerization is necessary but not sufficient for transduction. We also report nuclear uptake of GH both in vivo and in vitro, along with nuclear localization of the receptor and GH-binding protein (GHBP). This suggests that GH acts directly at the nucleus, and one possible target for this action is a rapid increase in transcription of C/EBP delta seen in 3T3-F442A cells in response to GH. This tyrosine kinase-dependent event may be an archetype for induction of other immediate early gene transcription factors which then interact to determine the programming of the subsequent transcriptional response to GH. 29 refs., 1 fig., 1 tab.

  4. Method of Promoting Single Crystal Growth During Melt Growth of Semiconductors

    NASA Technical Reports Server (NTRS)

    Su, Ching-Hua (Inventor)

    2013-01-01

    The method of the invention promotes single crystal growth during fabrication of melt growth semiconductors. A growth ampoule and its tip have a semiconductor source material placed therein. The growth ampoule is placed in a first thermal environment that raises the temperature of the semiconductor source material to its liquidus temperature. The growth ampoule is then transitioned to a second thermal environment that causes the semiconductor source material in the growth ampoule's tip to attain a temperature that is below the semiconductor source material's solidus temperature. The growth ampoule so-transitioned is then mechanically perturbed to induce single crystal growth at the growth ampoule's tip.

  5. USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.

    PubMed

    Madan, Babita; Walker, Matthew P; Young, Robert; Quick, Laura; Orgel, Kelly A; Ryan, Meagan; Gupta, Priti; Henrich, Ian C; Ferrer, Marc; Marine, Shane; Roberts, Brian S; Arthur, William T; Berndt, Jason D; Oliveira, Andre M; Moon, Randall T; Virshup, David M; Chou, Margaret M; Major, Michael B

    2016-05-24

    The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit. PMID:27162353

  6. B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

    PubMed Central

    O’Donovan, Kevin J.; Ma, Kaijie; Guo, Hengchang; Wang, Chen; Sun, Fang; Han, Seung Baek; Kim, Hyukmin; Wong, Jamie K.; Charron, Jean; Zou, Hongyan; Son, Young-Jin; He, Zhigang

    2014-01-01

    Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems. PMID:24733831

  7. Aspirin Promotes Oligodendroglial Differentiation Through Inhibition of Wnt Signaling Pathway.

    PubMed

    Huang, Nanxin; Chen, Dong; Wu, Xiyan; Chen, Xianjun; Zhang, Xuesi; Niu, Jianqin; Shen, Hai-Ying; Xiao, Lan

    2016-07-01

    Aspirin, one of the most commonly used anti-inflammatory drugs, has been recently reported to display multiple effects in the central nervous system (CNS), including neuroprotection and upregulation of ciliary neurotrophic factor (CNTF) expression in astrocytes. Although it was most recently reported that aspirin could promote the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) after white matter lesion, the underlying mechanisms remain unclear. To dissect the effects of aspirin on oligodendroglial development and explore possible mechanisms, we here demonstrated the following: (i) in vitro treatment of aspirin on OPC cultures significantly increased the number of differentiated oligodendrocytes (OLs) but had no effect on the number of proliferative OPCs, indicating that aspirin can promote OPC differentiation but not proliferation; (ii) in vivo treatment of aspirin on neonatal (P3) rats for 4 days led to a nearly twofold increase in the expression of myelin basic protein (MBP), devoid of change in OPC proliferaion, in the corpus callosum (CC); (iii) finally, aspirin treatment increased the phosphorylation level of β-catenin and counteracted Wnt signaling pathway synergist QS11-induced suppression on OPC differentiation. Together, our data show that aspirin can directly target oligodendroglial lineage cells and promote their differentiation through inhibition of Wnt/β-catenin signaling pathway. These findings suggest that aspirin may be a novel candidate for the treatment of demyelinating diseases. PMID:26059811

  8. Dopamine signaling promotes the xenobiotic stress response and protein homeostasis.

    PubMed

    Joshi, Kishore K; Matlack, Tarmie L; Rongo, Christopher

    2016-09-01

    Multicellular organisms encounter environmental conditions that adversely affect protein homeostasis (proteostasis), including extreme temperatures, toxins, and pathogens. It is unclear how they use sensory signaling to detect adverse conditions and then activate stress response pathways so as to offset potential damage. Here, we show that dopaminergic mechanosensory neurons in C. elegans release the neurohormone dopamine to promote proteostasis in epithelia. Signaling through the DA receptor DOP-1 activates the expression of xenobiotic stress response genes involved in pathogenic resistance and toxin removal, and these genes are required for the removal of unstable proteins in epithelia. Exposure to a bacterial pathogen (Pseudomonas aeruginosa) results in elevated removal of unstable proteins in epithelia, and this enhancement requires DA signaling. In the absence of DA signaling, nematodes show increased sensitivity to pathogenic bacteria and heat-shock stress. Our results suggest that dopaminergic sensory neurons, in addition to slowing down locomotion upon sensing a potential bacterial feeding source, also signal to frontline epithelia to activate the xenobiotic stress response so as to maintain proteostasis and prepare for possible infection. PMID:27261197

  9. Ethanolamine Signaling Promotes Salmonella Niche Recognition and Adaptation during Infection.

    PubMed

    Anderson, Christopher J; Clark, David E; Adli, Mazhar; Kendall, Melissa M

    2015-11-01

    Chemical and nutrient signaling are fundamental for all cellular processes, including interactions between the mammalian host and the microbiota, which have a significant impact on health and disease. Ethanolamine is an essential component of cell membranes and has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology. Here, we describe a virulence-regulating pathway in which the foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits ethanolamine signaling to recognize and adapt to distinct niches within the host. The bacterial transcription factor EutR promotes ethanolamine metabolism in the intestine, which enables S. Typhimurium to establish infection. Subsequently, EutR directly activates expression of the Salmonella pathogenicity island 2 in the intramacrophage environment, and thus augments intramacrophage survival. Moreover, EutR is critical for robust dissemination during mammalian infection. Our findings reveal that S. Typhimurium co-opts ethanolamine as a signal to coordinate metabolism and then virulence. Because the ability to sense ethanolamine is a conserved trait among pathogenic and commensal bacteria, our work indicates that ethanolamine signaling may be a key step in the localized adaptation of bacteria within their mammalian hosts. PMID:26565973

  10. Ethanolamine Signaling Promotes Salmonella Niche Recognition and Adaptation during Infection

    PubMed Central

    Anderson, Christopher J.; Clark, David E.; Adli, Mazhar; Kendall, Melissa M.

    2015-01-01

    Chemical and nutrient signaling are fundamental for all cellular processes, including interactions between the mammalian host and the microbiota, which have a significant impact on health and disease. Ethanolamine is an essential component of cell membranes and has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology. Here, we describe a virulence-regulating pathway in which the foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits ethanolamine signaling to recognize and adapt to distinct niches within the host. The bacterial transcription factor EutR promotes ethanolamine metabolism in the intestine, which enables S. Typhimurium to establish infection. Subsequently, EutR directly activates expression of the Salmonella pathogenicity island 2 in the intramacrophage environment, and thus augments intramacrophage survival. Moreover, EutR is critical for robust dissemination during mammalian infection. Our findings reveal that S. Typhimurium co-opts ethanolamine as a signal to coordinate metabolism and then virulence. Because the ability to sense ethanolamine is a conserved trait among pathogenic and commensal bacteria, our work indicates that ethanolamine signaling may be a key step in the localized adaptation of bacteria within their mammalian hosts. PMID:26565973

  11. Comparison of signaling interactions determining annual and perennial plant growth in response to low temperature

    PubMed Central

    Wingler, Astrid

    2015-01-01

    Low temperature inhibits plant growth despite the fact that considerable rates of photosynthetic activity can be maintained. Instead of lower rates of photosynthesis, active inhibition of cell division and expansion is primarily responsible for reduced growth. This results in sink limitation and enables plants to accumulate carbohydrates that act as compatible solutes or are stored throughout the winter to enable re-growth in spring. Regulation of growth in response to temperature therefore requires coordination with carbon metabolism, e.g., via the signaling metabolite trehalose-6-phosphate. The phytohormones gibberellin (GA) and jasmonate (JA) play an important role in regulating growth in response to temperature. Growth restriction at low temperature is mainly mediated by DELLA proteins, whose degradation is promoted by GA. For annual plants, it has been shown that the GA/DELLA pathway interacts with JA signaling and C-repeat binding factor dependent cold acclimation, but these interactions have not been explored in detail for perennials. Growth regulation in response to seasonal factors is, however, particularly important in perennials, especially at high latitudes. In autumn, growth cessation in trees is caused by shortening of the daylength in interaction with phytohormone signaling. In perennial grasses seasonal differences in the sensitivity to GA may enable enhanced growth in spring. This review provides an overview of the signaling interactions that determine plant growth at low temperature and highlights gaps in our knowledge, especially concerning the seasonality of signaling responses in perennial plants. PMID:25628637

  12. LRG1 promotes angiogenesis by modulating endothelial TGFß signalling

    PubMed Central

    Wang, Xiaomeng; Abraham, Sabu; McKenzie, Jenny A.G.; Jeffs, Natasha; Swire, Matthew; Tripathi, Vineeta B.; Luhmann, Ulrich F.O.; Lange, Clemens A.K.; Zhai, Zhenhua; Arthur, Helen M.; Bainbridge, James

    2013-01-01

    Aberrant neovascularisation contributes to diseases such as cancer, blindness and atherosclerosis and is the consequence of inappropriate angiogenic signalling. While many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explored the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology and uncovered an up-regulated gene, leucine-rich alpha-2-glycoprotein-1 (Lrg1), of previously unknown function. We show that in the presence of TGFβ1, LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGFβ accessory receptor endoglin which, in the presence of TGFβ1, results in promotion of the pro-angiogenic Smad1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a novel regulator of angiogenesis that mediates its effect through modulating TGFβ signalling. PMID:23868260

  13. Plant growth promotion by phosphate solubilizing bacteria.

    PubMed

    Zaidi, A; Khan, M S; Ahemad, M; Oves, M

    2009-09-01

    Most agronomic soils contain large reserves of total phosphorus [P], but the fixation and precipitation of P cause P deficiency, and in turn, restrict the growth of crops severely. Phosphorus replenishment, especially in sustainable production systems, remains a major challenge as it is mainly fertilizer-dependent. Though the use of chemical P fertilizers is obviously the best means to circumvent P deficiency in different agro-ecosystems, their use is always limited due to its spiralling cost. A greater interest has, therefore, been generated to find an alternative yet inexpensive technology that could provide sufficient P to plants while reducing the dependence on expensive chemical P fertilizers. Among the heterogeneous and naturally abundant microbes inhabiting the rhizosphere, the phosphate solubilizing microorganisms (PSM) including bacteria have provided an alternative biotechnological solution in sustainable agriculture to meet the P demands of plants. These organisms in addition to providing P to plants also facilitate plant growth by other mechanisms. Despite their different ecological niches and multiple functional properties, P-solubilizing bacteria have yet to fulfil their promise as commercial bio-inoculants. Current developments in our understanding of the functional diversity, rhizosphere colonizing ability, mode of actions and judicious application are likely to facilitate their use as reliable components in the management of sustainable agricultural systems. PMID:19789141

  14. Phase separation of signaling molecules promotes T cell receptor signal transduction.

    PubMed

    Su, Xiaolei; Ditlev, Jonathon A; Hui, Enfu; Xing, Wenmin; Banjade, Sudeep; Okrut, Julia; King, David S; Taunton, Jack; Rosen, Michael K; Vale, Ronald D

    2016-04-29

    Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling. PMID:27056844

  15. AHR signaling in prostate growth, morphogenesis, and disease

    PubMed Central

    Vezina, Chad M.; Lin, Tien-Min; Peterson, Richard E.

    2010-01-01

    Most evidence of aryl hydrocarbon receptor (AHR) signaling in prostate growth, morphogenesis, and disease stems from research using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to pharmacologically activate the AHR at various stages of development. This review discusses effects of TCDD on prostate morphogenesis and highlights interactions between AHR and other signaling pathways during normal and aberrant prostate growth. Although AHR signaling modulates estrogen and androgen signaling in other tissues, crosstalk between these steroid hormone receptors and AHR signaling cannot account for actions of TCDD on prostate morphogenesis. Instead, the AHR appears to act within a cooperative framework of developmental signals to regulate timing and patterning of prostate growth. Inappropriate activation of AHR signaling as a result of early life TCDD exposure disrupts the balance of these signals, impairs prostate morphogenesis, and has an imprinting effect on the developing prostate that predisposes to prostate disease in adulthood. Mechanisms of AHR signaling in prostate growth and disease are only beginning to be unraveled and recent studies have revealed its interactions with WNT5A, retinoic acid, fibroblast growth factor 10, and vascular endothelial growth factor signaling pathways. PMID:18977204

  16. ATR promotes cilia signalling: links to developmental impacts.

    PubMed

    Stiff, Tom; Casar Tena, Teresa; O'Driscoll, Mark; Jeggo, Penny A; Philipp, Melanie

    2016-04-15

    Mutations in ATR(ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder. Hitherto, the clinical manifestation of ATR deficiency has been attributed to its canonical role in DNA damage response signalling following replication fork stalling/collapse. Here, we show that ATR regulates cilia-dependent signalling in a manner that can be uncoupled from its function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia of slightly reduced length but are dramatically impaired in cilia-dependent signalling functions, including growth factor and Sonic hedgehog signalling. To better understand the developmental impact of ATR loss of function, we also used zebrafish as a model. Zebrafish embryos depleted of Atr resembled ATR-SS morphology, showed a modest but statistically significant reduction in cilia length and other morphological features indicative of cilia dysfunction. Additionally, they displayed defects in left-right asymmetry including ambiguous expression of southpaw, incorrectly looped hearts and randomized localization of internal organs including the pancreas, features typically conferred by cilia dysfunction. Our findings reveal a novel role for ATR in cilia signalling distinct from its canonical function during replication and strengthen emerging links between cilia function and development. PMID:26908596

  17. ATR promotes cilia signalling: links to developmental impacts

    PubMed Central

    Stiff, Tom; Casar Tena, Teresa; O'Driscoll, Mark; Jeggo, Penny A.; Philipp, Melanie

    2016-01-01

    Mutations in ATR (ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder. Hitherto, the clinical manifestation of ATR deficiency has been attributed to its canonical role in DNA damage response signalling following replication fork stalling/collapse. Here, we show that ATR regulates cilia-dependent signalling in a manner that can be uncoupled from its function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia of slightly reduced length but are dramatically impaired in cilia-dependent signalling functions, including growth factor and Sonic hedgehog signalling. To better understand the developmental impact of ATR loss of function, we also used zebrafish as a model. Zebrafish embryos depleted of Atr resembled ATR-SS morphology, showed a modest but statistically significant reduction in cilia length and other morphological features indicative of cilia dysfunction. Additionally, they displayed defects in left-right asymmetry including ambiguous expression of southpaw, incorrectly looped hearts and randomized localization of internal organs including the pancreas, features typically conferred by cilia dysfunction. Our findings reveal a novel role for ATR in cilia signalling distinct from its canonical function during replication and strengthen emerging links between cilia function and development. PMID:26908596

  18. STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation.

    PubMed

    Lemos, Henrique; Mohamed, Eslam; Huang, Lei; Ou, Rong; Pacholczyk, Gabriela; Arbab, Ali S; Munn, David; Mellor, Andrew L

    2016-04-15

    Cytosolic DNA sensing is an important process during the innate immune response that activates the stimulator of interferon genes (STING) adaptor and induces IFN-I. STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists, and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). Although STING also induced IDO in tumor-draining lymph nodes (TDLN) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8(+) T-cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL10 production in the TME. Depletion of CD8(+) T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8(+) T-cell effector functions during tumorigenesis. In contrast with native LLC tumors, STING signaling neither promoted growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity and how IDO inhibition can overcome this state by attenuating tumor tolerance. Furthermore, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials. Cancer Res; 76(8); 2076-81. ©2016 AACR. PMID:26964621

  19. Ack promotes tissue growth via phosphorylation and suppression of the Hippo pathway component Expanded

    PubMed Central

    Hu, Lianxin; Xu, Jiajun; Yin, Meng-Xin; Zhang, Liguo; Lu, Yi; Wu, Wenqing; Xue, Zhaoyu; Ho, Margaret S; Gao, Guanjun; Zhao, Yun; Zhang, Lei

    2016-01-01

    Non-receptor tyrosine kinase activated cdc42 kinase was reported to participate in several types of cancers in mammals. It is also believed to have an anti-apoptotic function in Drosophila. Here, we report the identification of Drosophila activated cdc42 kinase as a growth promoter and a novel Hippo signaling pathway regulator. We find that activated cdc42 kinase promotes tissue growth through modulating Yorkie activity. Furthermore, we demonstrate that activated cdc42 kinase interacts with Expanded and induces tyrosine phosphorylation of Expanded on multiple sites. We propose a model that activated cdc42 kinase negatively regulates Expanded by changing its phosphorylation status to promote tissue growth. Moreover, we show that ack genetically interacts with merlin and expanded. Thus, we identify Drosophila activated cdc42 kinase as a Hippo pathway regulator. PMID:27462444

  20. Plant growth promotion rhizobacteria in onion production.

    PubMed

    Colo, Josip; Hajnal-Jafari, Timea I; Durić, Simonida; Stamenov, Dragana; Hamidović, Saud

    2014-01-01

    The aim of the research was to examine the effect of rhizospheric bacteria Azotobacter chroococcum, Pseudomonas fluorescens (strains 1 and 2) and Bacillus subtilis on the growth and yield of onion and on the microorganisms in the rhizosphere of onion. The ability of microorganisms to produce indole-acetic acid (IAA), siderophores and to solubilize tricalcium phosphate (TCP) was also assessed. The experiment was conducted in field conditions, in chernozem type of soil. Bacillus subtilis was the best producer of IAA, whereas Pseudomonas fluorescens strains were better at producing siderophores and solubilizing phosphates. The longest seedling was observed with the application of Azotobacter chroococcum. The height of the plants sixty days after sowing was greater in all the inoculated variants than in the control. The highest onion yield was observed in Bacillus subtilis and Azotobacter chroococcum variants. The total number of bacteria and the number of Azotobacter chroococcum were larger in all the inoculated variants then in the control. The number of fungi decreased in most of the inoculated variants, whereas the number of actinomycetes decreased or remained the same. PMID:25033667

  1. The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

    PubMed Central

    Hunt, Liam C.; Xu, Beisi; Finkelstein, David; Fan, Yiping; Carroll, Patrick A.; Cheng, Pei-Feng; Eisenman, Robert N.; Demontis, Fabio

    2015-01-01

    Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors, but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we found that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX (Max-like protein X), which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin-like growth factor 2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned medium from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX-null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is manifested in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling. PMID:26584623

  2. Wnt/β-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression.

    PubMed

    Mir, R; Pradhan, S J; Patil, P; Mulherkar, R; Galande, S

    2016-03-31

    The chromatin organizer SATB1 has been implicated in the development and progression of multiple cancers including breast and colorectal cancers. However, the regulation and role of SATB1 in colorectal cancers is poorly understood. Here, we demonstrate that expression of SATB1 is induced upon hyperactivation of Wnt/β-catenin signaling and repressed upon depletion of TCF7L2 (TCF4) and β-catenin. Using several colorectal cancer cell line models and the APC min mutant zebrafish in vivo model, we established that SATB1 is a novel target of Wnt/β-catenin signaling. We show that direct binding of TCF7L2/β-catenin complex on Satb1 promoter is required for the regulation of SATB1. Moreover, SATB1 is sufficient to regulate the expression of β-catenin, members of TCF family, multiple downstream effectors and mediators of Wnt pathway. SATB1 potentiates the cellular changes and expression of key cancer-associated genes in non-aggressive colorectal cells, promotes their aggressive phenotype and tumorigenesis in vivo. Conversely, depletion of SATB1 from aggressive cells reprograms the expression of cancer-associated genes, reverses their cancer phenotype and reduces the potential of these cells to develop tumors in vivo. We also show that SATB1 and β-catenin bind to the promoters of TCF7L2 and the downstream targets of Wnt signaling and regulate their expression. Our findings suggest that SATB1 shares a feedback regulatory network with TCF7L2/β-catenin signaling and is required for Wnt signaling-dependent regulation of β-catenin. Collectively, these results provide unequivocal evidence to establish that SATB1 reprograms the expression of tumor growth- and metastasis-associated genes to promote tumorigenesis and functionally overlaps with Wnt signaling critical for colorectal cancer tumorigenesis. PMID:26165840

  3. TAF4 Inactivation Reveals the 3 Dimensional Growth Promoting Activities of Collagen 6A3

    PubMed Central

    Duluc, Isabelle; Vicaire, Serge; Philipps, Muriel; Freund, Jean-Noel; Davidson, Irwin

    2014-01-01

    Collagen 6A3 (Col6a3), a component of extracellular matrix, is often up-regulated in tumours and is believed to play a pro-oncogenic role. However the mechanisms of its tumorigenic activity are poorly understood. We show here that Col6a3 is highly expressed in densely growing mouse embryonic fibroblasts (MEFs). In MEFs where the TAF4 subunit of general transcription factor IID (TFIID) has been inactivated, elevated Col6a3 expression prevents contact inhibition promoting their 3 dimensional growth as foci and fibrospheres. Analyses of gene expression in densely growing Taf4−/− MEFs revealed repression of the Hippo pathway and activation of Wnt signalling. The Hippo activator Kibra/Wwc1 is repressed under dense conditions in Taf4−/− MEFs, leading to nuclear accumulation of the proliferation factor YAP1 in the cells forming 3D foci. At the same time, Wnt9a is activated and the Sfrp2 antagonist of Wnt signalling is repressed. Surprisingly, treatment of Taf4−/− MEFs with all-trans retinoic acid (ATRA) restores contact inhibition suppressing 3D growth. ATRA represses Col6a3 expression independently of TAF4 expression and Col6a3 silencing is sufficient to restore contact inhibition in Taf4−/− MEFs and to suppress 3D growth by reactivating Kibra expression to induce Hippo signalling and by inducing Sfrp2 expression to antagonize Wnt signalling. All together, these results reveal a critical role for Col6a3 in regulating both Hippo and Wnt signalling to promote 3D growth, and show that the TFIID subunit TAF4 is essential to restrain the growth promoting properties of Col6a3. Our data provide new insight into the role of extra cellular matrix components in regulating cell growth. PMID:24498316

  4. Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication.

    PubMed

    Dhawan, Sangeeta; Dirice, Ercument; Kulkarni, Rohit N; Bhushan, Anil

    2016-05-01

    Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-β (TGF-β) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent β-cell replication. Importantly, inhibition of TGF-β signaling can result in repression of the Ink4a/Arf locus, resulting in increased β-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-β pathway promote β-cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF-β signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-β signaling to promote human β-cell replication. PMID:26936960

  5. Growth-promotion of plants with depolymerized alginates by irradiation

    NASA Astrophysics Data System (ADS)

    Hien, Nguyen Quoc; Nagasawa, Naotsugu; Tham, Le Xuan; Yoshii, Fumio; Dang, Vo Huy; Mitomo, Hiroshi; Makuuchi, Keizo; Kume, Tamikazu

    2000-07-01

    Alginate has been degraded by gamma-ray irradiation from a Co-60 source in liquid state (aqueous solution) and in solid state (powder form). The irradiated alginate with a molecular weight less than 10 4 shows a strong effect on the growth-promotion of rice and peanut. Low concentration of degraded alginate from 4% solution irradiated at 100 kGy is effective for the growth-promotion of plants and the suitable concentrations are ca 50 ppm for rice and ca 100 ppm for peanut.

  6. [Characterization of growth-promoting rhizobacteria in Eucalyptus nitens seedlings].

    PubMed

    Angulo, Violeta C; Sanfuentes, Eugenio A; Rodríguez, Francisco; Sossa, Katherine E

    2014-01-01

    Rhizospheric and endophytic bacteria were isolated from the rizosphere and root tissue of Eucalyptus nitens. The objective of this work was to evaluate their capacity to promote growth in seedlings of the same species under greenhouse conditions. The isolates that improved seedling growth were identified and characterized by their capacity to produce indoleacetic acid (IAA), solubilize phosphates and increase 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity. One hundred and five morphologically different strains were isolated, 15 of which promoted E. nitens seedling growth, significantly increasing the height (50%), root length (45%) as well as the aerial and root dry weight (142% and 135% respectively) of the plants. Bacteria belonged to the genus Arthrobacter, Lysinibacillus, Rahnella and Bacillus. Isolates A. phenanthrenivorans 21 and B. cereus 113 improved 3.15 times the emergence of E. nitens after 12 days, compared to control samples. Among isolated R. aquatilis, 78 showed the highest production of IAA (97.5±2.87 μg/ml) in the presence of tryptophan and the highest solubilizer index (2.4) for phosphorus, while B. amyloliquefaciens 60 isolate was positive for ACC deaminase activity. Our results reveal the potential of the studied rhizobacteria as promoters of emergence and seedling growth of E. nitens, and their possible use as PGPR inoculants, since they have more than one mechanism associated with plant growth promotion. PMID:25576419

  7. Drosophila casein kinase 2 (CK2) promotes warts protein to suppress Yorkie protein activity for growth control.

    PubMed

    Hu, Lianxin; Huang, Hongling; Li, Jinhui; Yin, Meng-Xin; Lu, Yi; Wu, Wenqing; Zeng, Rong; Jiang, Jin; Zhao, Yun; Zhang, Lei

    2014-11-28

    Drosophila Hippo signaling regulates Wts activity to phosphorylate and inhibit Yki in order to control tissue growth. CK2 is widely expressed and involved in a variety of signaling pathways. In this study we report that Drosophila CK2 promotes Wts activity to phosphorylate and inhibit Yki activity, which is independent of Hpo-induced Wts promotion. In vivo, CK2 overexpression suppresses hpo mutant-induced expanded (Ex) up-regulation and overgrowth phenotype, whereas it cannot affect wts mutant. Consistent with this, knockdown of CK2 up-regulates Hpo pathway target expression. We also found that Drosophila CK2 is essential for tissue growth as a cell death inhibitor as knockdown of CK2 in the developing disc induces severe growth defects as well as caspase3 signals. Taken together, our results uncover a dual role of CK2; although its major role is promoting cell survive, it may potentially be a growth inhibitor as well. PMID:25320084

  8. Drosophila Casein Kinase 2 (CK2) Promotes Warts Protein to Suppress Yorkie Protein Activity for Growth Control*

    PubMed Central

    Hu, Lianxin; Huang, Hongling; Li, Jinhui; Yin, Meng-Xin; Lu, Yi; Wu, Wenqing; Zeng, Rong; Jiang, Jin; Zhao, Yun; Zhang, Lei

    2014-01-01

    Drosophila Hippo signaling regulates Wts activity to phosphorylate and inhibit Yki in order to control tissue growth. CK2 is widely expressed and involved in a variety of signaling pathways. In this study we report that Drosophila CK2 promotes Wts activity to phosphorylate and inhibit Yki activity, which is independent of Hpo-induced Wts promotion. In vivo, CK2 overexpression suppresses hpo mutant-induced expanded (Ex) up-regulation and overgrowth phenotype, whereas it cannot affect wts mutant. Consistent with this, knockdown of CK2 up-regulates Hpo pathway target expression. We also found that Drosophila CK2 is essential for tissue growth as a cell death inhibitor as knockdown of CK2 in the developing disc induces severe growth defects as well as caspase3 signals. Taken together, our results uncover a dual role of CK2; although its major role is promoting cell survive, it may potentially be a growth inhibitor as well. PMID:25320084

  9. Caffeine promotes wakefulness via dopamine signaling in Drosophila

    PubMed Central

    Nall, Aleksandra H.; Shakhmantsir, Iryna; Cichewicz, Karol; Birman, Serge; Hirsh, Jay; Sehgal, Amita

    2016-01-01

    Caffeine is the most widely-consumed psychoactive drug in the world, but our understanding of how caffeine affects our brains is relatively incomplete. Most studies focus on effects of caffeine on adenosine receptors, but there is evidence for other, more complex mechanisms. In the fruit fly Drosophila melanogaster, which shows a robust diurnal pattern of sleep/wake activity, caffeine reduces nighttime sleep behavior independently of the one known adenosine receptor. Here, we show that dopamine is required for the wake-promoting effect of caffeine in the fly, and that caffeine likely acts presynaptically to increase dopamine signaling. We identify a cluster of neurons, the paired anterior medial (PAM) cluster of dopaminergic neurons, as the ones relevant for the caffeine response. PAM neurons show increased activity following caffeine administration, and promote wake when activated. Also, inhibition of these neurons abrogates sleep suppression by caffeine. While previous studies have focused on adenosine-receptor mediated mechanisms for caffeine action, we have identified a role for dopaminergic neurons in the arousal-promoting effect of caffeine. PMID:26868675

  10. Steroid signaling promotes stem cell maintenance in the Drosophila testis.

    PubMed

    Li, Yijie; Ma, Qing; Cherry, Christopher M; Matunis, Erika L

    2014-10-01

    Stem cell regulation by local signals is intensely studied, but less is known about the effects of hormonal signals on stem cells. In Drosophila, the primary steroid twenty-hydroxyecdysone (20E) regulates ovarian germline stem cells (GSCs) but was considered dispensable for testis GSC maintenance. Male GSCs reside in a microenvironment (niche) generated by somatic hub cells and adjacent cyst stem cells (CySCs). Here, we show that depletion of 20E from adult males by overexpressing a dominant negative form of the Ecdysone receptor (EcR) or its heterodimeric partner ultraspiracle (usp) causes GSC and CySC loss that is rescued by 20E feeding, uncovering a requirement for 20E in stem cell maintenance. EcR and USP are expressed, activated and autonomously required in the CySC lineage to promote CySC maintenance, as are downstream genes ftz-f1 and E75. In contrast, GSCs non-autonomously require ecdysone signaling. Global inactivation of EcR increases cell death in the testis that is rescued by expression of EcR-B2 in the CySC lineage, indicating that ecdysone signaling supports stem cell viability primarily through a specific receptor isoform. Finally, EcR genetically interacts with the NURF chromatin-remodeling complex, which we previously showed maintains CySCs. Thus, although 20E levels are lower in males than females, ecdysone signaling acts through distinct cell types and effectors to ensure both ovarian and testis stem cell maintenance. PMID:25093968

  11. Macroporous hydrogels upregulate osteogenic signal expression and promote bone regeneration.

    PubMed

    Betz, Martha W; Yeatts, Andrew B; Richbourg, William J; Caccamese, John F; Coletti, Domenick P; Falco, Erin E; Fisher, John P

    2010-05-10

    The objective of this work was to investigate the effects of macroporous hydrogel architecture on the osteogenic signal expression and differentiation of human mesenchymal stem cells (hMSCs). In particular, we have proposed a tissue engineering approach for orbital bone repair based on a cyclic acetal biomaterial formed from 5-ethyl-5-(hydroxymethyl)-beta,beta-dimethyl-1,3-dioxane-2-ethanol diacrylate (EHD) and poly(ethylene glycol) diacrylate (PEGDA). The EHD monomer and PEGDA polymer may be fabricated into macroporous EH-PEG hydrogels by radical polymerization and subsequent porogen leaching, a novel technique for hydrophilic gels. We hypothesized that EH-PEG hydrogel macroporosity facilitates intercellular signaling among hMSCs. To investigate this phenomenon, hMSCs were loaded into EH-PEG hydrogels with varying pore size and porosity. The viability of hMSCs, the expression of bone morphogenetic protein-2 (BMP-2), BMP receptor type 1A, and BMP receptor type 2 by hMSCs, and the differentiation of hMSCs were then assessed. Results demonstrate that macroporous EH-PEG hydrogels support hMSCs and that this macroporous environment promotes a dramatic increase in BMP-2 expression by hMSCs. This upregulation of BMP-2 expression is associated by a more rapid hMSC differentiation, as measured by alkaline phosphatase expression. Altering hMSC interactions with the EH-PEG hydrogel surface, by the addition of fibronectin, did not appear to augment BMP-2 expression. We therefore speculate that EH-PEG hydrogel macroporosity facilitates autocrine and paracrine signaling by localizing endogenously expressed factors within the hydrogel's pores and thus promotes hMSC osteoblastic differentiation and bone regeneration. PMID:20345129

  12. Role of Arachidonic Acid in Promoting Hair Growth

    PubMed Central

    Munkhbayar, Semchin; Jang, Sunhyae; Cho, A-Ri; Choi, Soon-Jin; Shin, Chang Yup; Eun, Hee Chul; Kim, Kyu Han

    2016-01-01

    Background Arachidonic acid (AA) is an omega-6 polyunsaturated fatty acid present in all mammalian cell membranes, and involved in the regulation of many cellular processes, including cell survival, angiogenesis, and mitogenesis. The dermal papilla, composed of specialized fibroblasts located in the bulb of the hair follicle, contributes to the control of hair growth and the hair cycle. Objective This study investigated the effect of AA on hair growth by using in vivo and in vitro models. Methods The effect of AA on human dermal papilla cells (hDPCs) and hair shaft elongation was evaluated by MTT assay and hair follicle organ culture, respectively. The expression of various growth and survival factors in hDPCs were investigated by western blot or immunohistochemistry. The ability of AA to induce and prolong anagen phase in C57BL/6 mice was analyzed. Results AA was found to enhance the viability of hDPCs and promote the expression of several factors responsible for hair growth, including fibroblast growth factor-7 (FGF-7) and FGF-10. Western blotting identified the role of AA in the phosphorylation of various transcription factors (ERK, CREB, and AKT) and increased expression of Bcl-2 in hDPCs. In addition, AA significantly promoted hair shaft elongation, with increased proliferation of matrix keratinocytes, during ex vivo hair follicle culture. It was also found to promote hair growth by induction and prolongation of anagen phase in telogen-stage C57BL/6 mice. Conclusion This study concludes that AA plays a role in promoting hair growth by increasing the expression of growth factors in hDPCs and enhancing follicle proliferation and survival. PMID:26848219

  13. EphA2 overexpression promotes ovarian cancer growth

    PubMed Central

    Lu, Chunhua; Shahzad, Mian M.K.; Wang, Hua; Landen, Charles N.; Kim, Seung W.; Allen, Julie; Nick, Alpa M.; Jennings, Nicholas; Kinch, Michael S.; Bar-Eli, Menashe; Sood, Anil K.

    2009-01-01

    Background Silencing EphA2 has been shown to result in anti-tumor efficacy. However, it is not known whether increasing EphA2 expression specifically results in increased tumor growth and progression. We examined the effects of stable EphA2 transfection into poorly invasive ovarian cancer cells with regard to in vitro invasive and in vivo metastatic potential. Results In low cell density, EphA2-overexpressing A2780 cells (A2780-EphA2) displayed less cell-cell contact, increased cell-extracellular matrix (ECM) attachment and anchorage-independent cell growth compared to empty vector controls. There was no significant effect on anchorage-dependent cell proliferation, migration or invasion. Increased expression of EphA2 promoted tumor growth and enhanced the metastatic potential in A2780-EphA2 human ovarian cancer xenografts. The overexpression of EphA2 resulted in enhanced microvessel density (MVD), but had no effect on tumor cell proliferation. Methods EphA2 gene was introduced into A2780 cells by retroviral infection. The effects of increased EphA2 expression were examined on cellular morphology, and anchorage-dependent and independent cell growth. Furthermore, the effect of EphA2 overexpression on metastatic ability was determined using an orthotopic nude mouse model of ovarian carcinoma. Conclusions EphA2 promotes tumor growth by enhancing cell-ECM adhesion, increasing anchorage-independent growth and promoting angiogenesis. PMID:18443431

  14. Biochar Treatment Resulted in a Combined Effect on Soybean Growth Promotion and a Shift in Plant Growth Promoting Rhizobacteria

    PubMed Central

    Egamberdieva, Dilfuza; Wirth, Stephan; Behrendt, Undine; Abd_Allah, Elsayed F.; Berg, Gabriele

    2016-01-01

    The application of biochar to soil is considered to have the potential for long-term soil carbon sequestration, as well as for improving plant growth and suppressing soil pathogens. In our study we evaluated the effect of biochar on the plant growth of soybeans, as well as on the community composition of root-associated bacteria with plant growth promoting traits. Two types of biochar, namely, maize biochar (MBC), wood biochar (WBC), and hydrochar (HTC) were used for pot experiments to monitor plant growth. Soybean plants grown in soil amended with HTC char (2%) showed the best performance and were collected for isolation and further characterization of root-associated bacteria for multiple plant growth promoting traits. Only HTC char amendment resulted in a statistically significant increase in the root and shoot dry weight of soybeans. Interestingly, rhizosphere isolates from HTC char amended soil showed higher diversity than the rhizosphere isolates from the control soil. In addition, a higher proportion of isolates from HTC char amended soil compared with control soil was found to express plant growth promoting properties and showed antagonistic activity against one or more phytopathogenic fungi. Our study provided evidence that improved plant growth by biochar incorporation into soil results from the combination of a direct effect that is dependent on the type of char and a microbiome shift in root-associated beneficial bacteria. PMID:26941730

  15. Biochar Treatment Resulted in a Combined Effect on Soybean Growth Promotion and a Shift in Plant Growth Promoting Rhizobacteria.

    PubMed

    Egamberdieva, Dilfuza; Wirth, Stephan; Behrendt, Undine; Abd Allah, Elsayed F; Berg, Gabriele

    2016-01-01

    The application of biochar to soil is considered to have the potential for long-term soil carbon sequestration, as well as for improving plant growth and suppressing soil pathogens. In our study we evaluated the effect of biochar on the plant growth of soybeans, as well as on the community composition of root-associated bacteria with plant growth promoting traits. Two types of biochar, namely, maize biochar (MBC), wood biochar (WBC), and hydrochar (HTC) were used for pot experiments to monitor plant growth. Soybean plants grown in soil amended with HTC char (2%) showed the best performance and were collected for isolation and further characterization of root-associated bacteria for multiple plant growth promoting traits. Only HTC char amendment resulted in a statistically significant increase in the root and shoot dry weight of soybeans. Interestingly, rhizosphere isolates from HTC char amended soil showed higher diversity than the rhizosphere isolates from the control soil. In addition, a higher proportion of isolates from HTC char amended soil compared with control soil was found to express plant growth promoting properties and showed antagonistic activity against one or more phytopathogenic fungi. Our study provided evidence that improved plant growth by biochar incorporation into soil results from the combination of a direct effect that is dependent on the type of char and a microbiome shift in root-associated beneficial bacteria. PMID:26941730

  16. Growth promoting effect of hyaluronan synthesis promoting substances on Japanese eel leptocephali.

    PubMed

    Kawakami, Yutaka; Nomura, Kazuharu; Tanaka, Hideki

    2014-01-01

    Hyaluronans (HAs) are glycosaminoglycans produced in the bodies of Anguilliform and Elopiform leptocephali, and play a role in metabolic energy. In mammals, HA synthesis-promoting substances (HASPS) up-regulate the expression of HA synthase (HAS) and increase the amount of HA in the body. In this study, Japanese eel leptocephali were fed a HASPS containing diet. We analyzed HAS1s and HAS2 expression, HA content, and their influence on growth. HASPS extracted from Grifola frondosa promoted HAS1s and HAS2 mRNA and HA content. Other than mammals, these results are first reported in vertebrate. Moreover, HASPS extracted from G. frondosa promoted leptocephalus growth. The relationship between growth and HA in the leptocephali is not yet clear. However, based on our results we hypothesize that HA is involved in the storage of energy, which is metabolized to sugars when needed for metabolic energy. PMID:24896609

  17. The impact of growth promoters on muscle growth and the potential consequences for meat quality.

    PubMed

    Parr, Tim; Mareko, Molebeledi H D; Ryan, Kevin J P; Hemmings, Krystal M; Brown, David M; Brameld, John M

    2016-10-01

    To meet the demands of increased global meat consumption, animal production systems will have to become more efficient, or at least maintain the current efficiency utilizing feed ingredients that are not also used for human consumption. Use of growth promoters is a potential option for increasing production animal feed efficiency and increased muscle growth. The objective of this manuscript is to describe the mechanisms by which the growth promoters, beta-adrenergic agonists and growth hormone, mediate their effects, with specific consideration of the aspects which have implications for meat quality. PMID:27179582

  18. Growth-Promoting Relationships with Children and Youth

    ERIC Educational Resources Information Center

    Spencer, Renée; Rhodes, Jean E.

    2014-01-01

    At the heart of afterschool programs are the relationships that form between the children and youth who participate in these programs and the adults who lead them. To be effective, adults working in afterschool settings must be able to engage youth in growth-promoting relationships. This article identifies and describes four foundational ways of…

  19. Red clover: An alternative to antibiotic growth promoters?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A series of experiments were conducted at the Forage-Animal Production Research Unit to discover a growth-promoting natural product from red clover (Trifolium pratense). Previously published work included a bioassay for antimicrobial activity of phytochemicals. The bioassay was used to discover th...

  20. Promoting Moral Growth through Pluralism and Social Justice Education

    ERIC Educational Resources Information Center

    Stewart, Dafina Lazarus

    2012-01-01

    Issues of morality, including deciding among competing values and negotiating obligations to self and community, are pervasive and saturate many aspects of life. This article explores the role of educating for pluralism and social justice in promoting moral growth among college students. James Rest's four-component model of moral maturity frames…

  1. Plant Growth-Promoting Bacteria: Mechanisms and Applications

    PubMed Central

    Glick, Bernard R.

    2012-01-01

    The worldwide increases in both environmental damage and human population pressure have the unfortunate consequence that global food production may soon become insufficient to feed all of the world's people. It is therefore essential that agricultural productivity be significantly increased within the next few decades. To this end, agricultural practice is moving toward a more sustainable and environmentally friendly approach. This includes both the increasing use of transgenic plants and plant growth-promoting bacteria as a part of mainstream agricultural practice. Here, a number of the mechanisms utilized by plant growth-promoting bacteria are discussed and considered. It is envisioned that in the not too distant future, plant growth-promoting bacteria (PGPB) will begin to replace the use of chemicals in agriculture, horticulture, silviculture, and environmental cleanup strategies. While there may not be one simple strategy that can effectively promote the growth of all plants under all conditions, some of the strategies that are discussed already show great promise. PMID:24278762

  2. Talk That Teaches: How to Promote Professional Dialogue and Growth

    ERIC Educational Resources Information Center

    Gibbons, Lynsey; Knapp, Melinda

    2015-01-01

    What types of talk promote teachers' professional growth? In the following vignettes, 4th-grade teachers and instructional leaders examine student work and observe classroom instruction. These learning designs encourage teachers to talk in ways that develop a shared understanding of teaching, which is instrumental to their professional growth…

  3. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals.

    PubMed

    Shao, Jian-Su; Cheng, Su-Li; Pingsterhaus, Joyce M; Charlton-Kachigian, Nichole; Loewy, Arleen P; Towler, Dwight A

    2005-05-01

    In diabetic LDLR-/- mice, an ectopic BMP2-Msx2 gene regulatory program is upregulated in association with vascular calcification. We verified the procalcific actions of aortic Msx2 expression in vivo. CMV-Msx2 transgenic (CMV-Msx2Tg(+)) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates. On high-fat diets, CMV-Msx2Tg(+) mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media. This corresponded to regions of Msx2 immunoreactivity in adjacent adventitial myofibroblasts, suggesting a potential paracrine osteogenic signal. To better understand Msx2-regulated calcification, we studied actions in 10T1/2 cells. We found that conditioned media from Msx2-transduced 10T1/2 cells (Msx2-CM) is both pro-osteogenic and adipostatic; these features are characteristic of Wnt signaling. Msx2-CM stimulated Wnt-dependent TCF/LEF transcription, and Msx2-transduced cells exhibited increased nuclear beta-catenin localization with concomitant alkaline phosphatase induction. Msx2 upregulated Wnt3a and Wnt7a but downregulated expression of the canonical inhibitor Dkk1. Dkk1 treatment reversed osteogenic and adipostatic actions of Msx2. Teriparatide, a PTH1R agonist that inhibits murine vascular calcification, suppressed vascular BMP2-Msx2-Wnt signaling. Analyses of CMV-Msx2Tg(+) mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts; moreover, TOPGAL(+) (Wnt reporter); CMV-Msx2Tg(+) mice exhibited augmented aortic LacZ expression. Thus, Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals. PMID:15841209

  4. [Antibiotic growth promoters for the view of animal nutrition].

    PubMed

    Kamphues, J

    1999-01-01

    From 01. 07./09. 1999 on six further antibiotic growth promoters have been banned--with only four substances remaining in this group of feed additives. Therefore, the discussion on a possible induction of bacterial resistance by antibiotic growth promoters, especially in potentially pathogenic bacteria, will sooner or later come to an end which is not least in the interest of the reputation of animal husbandry and food of animal origin. Unfortunately, no short-term solution for health problems by legislation--especially in the gastrointestinal tract--during rearing and the beginning of the fattening period is possible as experiences in Sweden have distinctively shown. Anyway, growth promoting feed additives were not a cure-all of rearing problems, in spite of their use considerable amounts of antibiotics were prescribed during this period. But growth promoters (especially chinoxalines) were most suitable for the prophylaxis of a microbial imbalance in the gastrointestinal tract. Therefore, after the ban of these effective representatives of feed additives the amount of prescribed antimicrobial drugs for metaphylaxis and therapy should be critically observed. The questions of practicable alternatives will be primarily addressed to the fields of animal nutrition, veterinary medicine and feed industry. To answer these questions and to evolve new solutions (as well as to check their suitability in practice) is considerably more intricate than simply to ban these substances which is more attractive for the media, however. It is no progressive solution to give up antimicrobial growth promoters as feed additives and to use the same substances (for example olaquindox) as therapeutics now (prescribed by veterinarians) or to switch to zincoxide or copper (in a dosage high above all nutrient requirements) in order to prevent postweaning problems due to E. coli. But one has to take into consideration the reasons for the use of antibiotics (growth promoters and therapeutics) or

  5. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors.

    PubMed

    Wu, J; Patmore, D M; Jousma, E; Eaves, D W; Breving, K; Patel, A V; Schwartz, E B; Fuchs, J R; Cripe, T P; Stemmer-Rachamimov, A O; Ratner, N

    2014-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics. PMID:23318430

  6. Ras-activated Dsor1 promotes Wnt signaling in Drosophila development.

    PubMed

    Hall, Eric T; Verheyen, Esther M

    2015-12-15

    Wnt/Wingless (Wg) and Ras-MAPK signaling both play fundamental roles in growth and cell fate determination, and when dysregulated, can lead to tumorigenesis. Several conflicting modes of interaction between Ras-MAPK and Wnt signaling have been identified in specific cellular contexts, causing synergistic or antagonistic effects on target genes. We find novel evidence that the Drosophila homolog of the dual specificity kinases MEK1/2 (also known as MAP2K1/2), Downstream of Raf1 (Dsor1), is required for Wnt signaling. Knockdown of Dsor1 results in loss of Wg target gene expression, as well as reductions in stabilized Armadillo (Arm; Drosophila β-catenin). We identify a close physical interaction between Dsor1 and Arm, and find that catalytically inactive Dsor1 causes a reduction in active Arm. These results suggest that Dsor1 normally counteracts the Axin-mediated destruction of Arm. We find that Ras-Dsor1 activity is independent of upstream activation by EGFR, and instead it appears to be activated by the insulin-like growth factor receptor to promote Wg signaling. Taken together, our results suggest that there is a new crosstalk pathway between insulin and Wg signaling that is mediated by Dsor1. PMID:26542023

  7. Zoospore interspecific signaling promotes plant infection by Phytophthora

    PubMed Central

    2010-01-01

    Background Oomycetes attack a huge variety of economically and ecologically important plants. These pathogens release, detect and respond to signal molecules to coordinate their communal behaviors including the infection process. When signal molecules are present at or above threshold level, single zoospores can infect plants. However, at the beginning of a growing season population densities of individual species are likely below those required to reach a quorum and produce threshold levels of signal molecules to trigger infection. It is unclear whether these molecules are shared among related species and what their chemistries are. Results Zoospore-free fluids (ZFF) from Phytophthora capsici, P. hydropathica, P. nicotianae (ZFFnic), P. sojae (ZFFsoj) and Pythium aphanidermatum were cross tested for stimulating plant infection in three pathosystems. All ZFFs tested significantly increased infection of Catharanthus roseus by P. nicotianae. Similar cross activities were observed in infection of Lupinus polyphyllus and Glycine max by P. sojae. Only ZFFnic and ZFFsoj cross induced zoospore aggregation at a density of 2 × 103 ml-1. Pure autoinducer-2 (AI-2), a component in ZFF, caused zoospore lysis of P. nicotianae before encystment and did not stimulate plant infection at concentrations from 0.01 to 1000 μM. P. capsici transformants with a transiently silenced AI-2 synthase gene, ribose phosphate isomerase (RPI), infected Capsicum annuum seedlings at the same inoculum concentration as the wild type. Acyl-homoserine lactones (AHLs) were not detected in any ZFFs. After freeze-thaw treatments, ZFF remained active in promoting plant infection but not zoospore aggregation. Heat treatment by boiling for 5 min also did not affect the infection-stimulating property of ZFFnic. Conclusion Oomycetes produce and use different molecules to regulate zoospore aggregation and plant infection. We found that some of these signal molecules could act in an inter-specific manner

  8. Plant growth-promoting bacteria as inoculants in agricultural soils.

    PubMed

    Souza, Rocheli de; Ambrosini, Adriana; Passaglia, Luciane M P

    2015-12-01

    Plant-microbe interactions in the rhizosphere are the determinants of plant health, productivity and soil fertility. Plant growth-promoting bacteria (PGPB) are bacteria that can enhance plant growth and protect plants from disease and abiotic stresses through a wide variety of mechanisms; those that establish close associations with plants, such as the endophytes, could be more successful in plant growth promotion. Several important bacterial characteristics, such as biological nitrogen fixation, phosphate solubilization, ACC deaminase activity, and production of siderophores and phytohormones, can be assessed as plant growth promotion (PGP) traits. Bacterial inoculants can contribute to increase agronomic efficiency by reducing production costs and environmental pollution, once the use of chemical fertilizers can be reduced or eliminated if the inoculants are efficient. For bacterial inoculants to obtain success in improving plant growth and productivity, several processes involved can influence the efficiency of inoculation, as for example the exudation by plant roots, the bacterial colonization in the roots, and soil health. This review presents an overview of the importance of soil-plant-microbe interactions to the development of efficient inoculants, once PGPB are extensively studied microorganisms, representing a very diverse group of easily accessible beneficial bacteria. PMID:26537605

  9. Plant growth-promoting bacteria as inoculants in agricultural soils

    PubMed Central

    de Souza, Rocheli; Ambrosini, Adriana; Passaglia, Luciane M.P.

    2015-01-01

    Abstract Plant-microbe interactions in the rhizosphere are the determinants of plant health, productivity and soil fertility. Plant growth-promoting bacteria (PGPB) are bacteria that can enhance plant growth and protect plants from disease and abiotic stresses through a wide variety of mechanisms; those that establish close associations with plants, such as the endophytes, could be more successful in plant growth promotion. Several important bacterial characteristics, such as biological nitrogen fixation, phosphate solubilization, ACC deaminase activity, and production of siderophores and phytohormones, can be assessed as plant growth promotion (PGP) traits. Bacterial inoculants can contribute to increase agronomic efficiency by reducing production costs and environmental pollution, once the use of chemical fertilizers can be reduced or eliminated if the inoculants are efficient. For bacterial inoculants to obtain success in improving plant growth and productivity, several processes involved can influence the efficiency of inoculation, as for example the exudation by plant roots, the bacterial colonization in the roots, and soil health. This review presents an overview of the importance of soil-plant-microbe interactions to the development of efficient inoculants, once PGPB are extensively studied microorganisms, representing a very diverse group of easily accessible beneficial bacteria. PMID:26537605

  10. Plant Growth Promoting Rhizobacteria and Mycorrhizal Fungi in Sustainable Agriculture and Forestry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant-growth promoting rhizobacteria (PGPR) encourage plant growth by producing growth regulators, facilitating nutrient uptake, accelerating mineralization, reducing plant stress, stimulating nodulation, providing nitrogen fixation, promoting mycorrhizal fungi, suppressing plant diseases, and funct...

  11. Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation.

    PubMed

    Yang, Shenghong; Imamura, Yu; Jenkins, Russell W; Cañadas, Israel; Kitajima, Shunsuke; Aref, Amir; Brannon, Arthur; Oki, Eiji; Castoreno, Adam; Zhu, Zehua; Thai, Tran; Reibel, Jacob; Qian, Zhirong; Ogino, Shuji; Wong, Kwok K; Baba, Hideo; Kimmelman, Alec C; Pasca Di Magliano, Marina; Barbie, David A

    2016-06-01

    Autophagy promotes tumor progression downstream of oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IκB kinase (IKK)-related kinase TBK1 in vivo, associated with increased neutrophil and T-cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFNγ signaling and involves JAK pathway activation. Treatment with the TBK1/IKKε/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting. Cancer Immunol Res; 4(6); 520-30. ©2016 AACR. PMID:27068336

  12. Rac1 promotes chondrogenesis by regulating STAT3 signaling pathway.

    PubMed

    Kim, Hyoin; Sonn, Jong Kyung

    2016-09-01

    The small GTPase protein Rac1 is involved in a wide range of biological processes including cell differentiation. Previously, Rac1 was shown to promote chondrogenesis in micromass cultures of limb mesenchyme. However, the pathways mediating Rac1's role in chondrogenesis are not fully understood. This study aimed to explore the molecular mechanisms by which Rac1 regulates chondrogenic differentiation. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased as chondrogenesis proceeded in micromass cultures of chick wing bud mesenchyme. Inhibition of Rac1 with NSC23766, janus kinase 2 (JAK2) with AG490, or STAT3 with stattic inhibited chondrogenesis and reduced phosphorylation of STAT3. Conversely, overexpression of constitutively active Rac1 (Rac L61) increased phosphorylation of STAT3. Rac L61 expression resulted in increased expression of interleukin 6 (IL-6), and treatment with IL-6 increased phosphorylation of STAT3. NSC23766, AG490, and stattic prohibited cell aggregation, whereas expression of Rac L61 increased cell aggregation, which was reduced by stattic treatment. Our studies indicate that Rac1 induces STAT3 activation through expression and action of IL-6. Overexpression of Rac L61 increased expression of bone morphogenic protein 4 (BMP4). BMP4 promoted chondrogenesis, which was inhibited by K02288, an activin receptor-like kinase-2 inhibitor, and increased phosphorylation of p38 MAP kinase. Overexpression of Rac L61 also increased phosphorylation of p38 MAPK, which was reduced by K02288. These results suggest that Rac1 activates STAT3 by expression of IL-6, which in turn increases expression and activity of BMP4, leading to the promotion of chondrogenesis. PMID:27306109

  13. Ecdysone promotes growth of imaginal discs through the regulation of Thor in D. melanogaster.

    PubMed

    Herboso, Leire; Oliveira, Marisa M; Talamillo, Ana; Pérez, Coralia; González, Monika; Martín, David; Sutherland, James D; Shingleton, Alexander W; Mirth, Christen K; Barrio, Rosa

    2015-01-01

    Animals have a determined species-specific body size that results from the combined action of hormones and signaling pathways regulating growth rate and duration. In Drosophila, the steroid hormone ecdysone controls developmental transitions, thereby regulating the duration of the growth period. Here we show that ecdysone promotes the growth of imaginal discs in mid-third instar larvae, since imaginal discs from larvae with reduced or no ecdysone synthesis are smaller than wild type due to smaller and fewer cells. We show that insulin-like peptides are produced and secreted normally in larvae with reduced ecdysone synthesis, and upstream components of insulin/insulin-like signaling are activated in their discs. Instead, ecdysone appears to regulate the growth of imaginal discs via Thor/4E-BP, a negative growth regulator downstream of the insulin/insulin-like growth factor/Tor pathways. Discs from larvae with reduced ecdysone synthesis have elevated levels of Thor, while mutations in Thor partially rescue their growth. The regulation of organ growth by ecdysone is evolutionarily conserved in hemimetabolous insects, as shown by our results obtained using Blattella germanica. In summary, our data provide new insights into the relationship between components of the insulin/insulin-like/Tor and ecdysone pathways in the control of organ growth. PMID:26198204

  14. Ecdysone promotes growth of imaginal discs through the regulation of Thor in D. melanogaster

    PubMed Central

    Herboso, Leire; Oliveira, Marisa M.; Talamillo, Ana; Pérez, Coralia; González, Monika; Martín, David; Sutherland, James D.; Shingleton, Alexander W.; Mirth, Christen K.; Barrio, Rosa

    2015-01-01

    Animals have a determined species-specific body size that results from the combined action of hormones and signaling pathways regulating growth rate and duration. In Drosophila, the steroid hormone ecdysone controls developmental transitions, thereby regulating the duration of the growth period. Here we show that ecdysone promotes the growth of imaginal discs in mid-third instar larvae, since imaginal discs from larvae with reduced or no ecdysone synthesis are smaller than wild type due to smaller and fewer cells. We show that insulin-like peptides are produced and secreted normally in larvae with reduced ecdysone synthesis, and upstream components of insulin/insulin-like signaling are activated in their discs. Instead, ecdysone appears to regulate the growth of imaginal discs via Thor/4E-BP, a negative growth regulator downstream of the insulin/insulin-like growth factor/Tor pathways. Discs from larvae with reduced ecdysone synthesis have elevated levels of Thor, while mutations in Thor partially rescue their growth. The regulation of organ growth by ecdysone is evolutionarily conserved in hemimetabolous insects, as shown by our results obtained using Blattella germanica. In summary, our data provide new insights into the relationship between components of the insulin/insulin-like/Tor and ecdysone pathways in the control of organ growth. PMID:26198204

  15. Bacteria as growth-promoting agents for citrus rootstocks.

    PubMed

    Giassi, Valdionei; Kiritani, Camila; Kupper, Katia Cristina

    2016-09-01

    The microbial community plays an essential role in maintaining the ecological balance of soils. Interactions between microorganisms and plants have a major influence on the nutrition and health of the latter, and growth-promoting rhizobacteria can be used to improve plant development through a wide range of mechanisms. Therefore, the objective of the present study was to evaluate bacteria as growth-promoting agents for citrus rootstocks. A total of 30 bacterial isolates (11 of Bacillus spp., 11 actinobacteria, and 8 lactic acid bacteria) were evaluated in vitro for indoleacetic acid production, phosphate solubilization, and nitrogen (N) fixation. In vivo testing consisted of growth promotion trials of the bacterial isolates that yielded the best results on in vitro tests with three rootstocks: Swingle citrumelo [Citrus×paradisi Macfad cv. Duncan×Poncirus trifoliata (L.) Raf.], Sunki mandarin (Citrus sunki Hort. ex Tan), and rangpur (Citrus×limonia Osbeck). The parameters of interest were height, number of leaves, stem diameter, shoot and root dry mass, and total dry mass at 150days after germination. The results showed that most bacterial isolates were capable of IAA production. Only one lactic acid bacterium isolate (BL06) solubilized phosphate, with a high solubilization index (PSI>3). In the actinobacteria group, isolates ACT01 (PSI=2.09) and ACT07 (PSI=2.01) exhibited moderate phosphate-solubilizing properties. Of the Bacillus spp. isolates, only CPMO6 and BM17 solubilized phosphate. The bacterial isolates that most fixated nitrogen were BM17, ACT11, and BL24. In the present study, some bacteria were able to promote growth of citrus rootstocks; however, this response was dependent on plant genotype and isolate. Bacillus spp. BM16 and CPMO4 were able to promote growth of Swingle citrumelo. In Sunki mandarin plants, the best treatment results were obtained with BM17 (Bacillus sp.) and ACT11 (actinobacteria). For Rangpur lime rootstock, only BM05 (Bacillus sp

  16. PEGylation of a Maltose Biosensor Promotes Enhanced Signal Response

    SciTech Connect

    Dattelbaum, Andrew; Baker, Gary A; Fox, John M; Iyer, Srinivas; Dattelbaum, Jonathan

    2009-01-01

    A robust method to immobilize a maltose biosensor is described using an engineered maltose periplasmic binding protein (PBP) covalently coupled to NBDamide, an environmentally sensitive fluorophore. A mesoporous silica sol-gel derived from diglycerylsilane (DGS) was constructed to embed the maltose biosensor, and the ligand reporting fluorescence properties were meas red. When sequestered in the DGS-derived silica matrix, the biosensor retained maltose-dependent fluorescence sensing capability with micromolar affinity, which is consistent with the protein free in solution. The MBP-NBD conjugate was further modified by covalent conjugation with poly(ethylene glycol)-5000 (PEG) to promote the retention of water molecules around the protein and to reduce possible steric effects between the silica matrix and protein. Bioconjugation with PEG molecules does not significantly affect the signaling response of the protein in solution. When immobilized in the DGS polymer, a consistent increase in fluorescence intensity was observed as compared to the protein not functionalized with PEG. To our knowledge, this report presents the first successful method to embed a PBP biosensor in a polymerized matrix and retain signaling response using an environmentally sensitive probe. The immobilization method presented here should be easily adaptable to all conformation-dependent biosensors.

  17. TGFβ signaling promotes juvenile granulosa cell tumorigenesis by suppressing apoptosis.

    PubMed

    Mansouri-Attia, Nadéra; Tripurani, Swamy K; Gokul, Nisha; Piard, Hermann; Anderson, Matthew L; Eldin, Karen; Pangas, Stephanie A

    2014-11-01

    Molecular changes that give rise to granulosa cell tumors of the ovary are not well understood. Previously, we showed that deletion in granulosa cells of the bone morphogenetic protein receptor-signaling transcription factors, Smad1 and Smad5, causes development of metastatic granulosa cell tumors that phenocopy the juvenile form of granulosa cell tumors (JGCTs) in humans. The TGFβ-SMAD2/3 pathway is active in JGCTs, but its role is unknown. We tested the in vivo contribution of TGFβ-SMAD signaling to JGCT development by genetically deleting the common Smad4 from Smad1/5 double knockout mice. Smad1/5/4 triple knockout mice were sterile and had significantly increased survival and delayed tumor development compared to those for the Smad1/5 double knockout mice. The few tumors that did develop were smaller, showed no evidence of metastasis, and had increased apoptosis. In the human JGCT cell line COV434, TGFβ1 increased viability by inhibiting apoptosis through a TGFβ type I receptor-dependent repression of caspase activity and inhibition of poly(ADP-ribose) polymerase cleavage. These data support a tumor-promoting function of TGFβ in JGCTs through its ability to repress apoptosis. PMID:25243859

  18. Fibroblast growth factor signals regulate a wave of Hedgehog activation that is essential for coronary vascular development.

    PubMed

    Lavine, Kory J; White, Andrew C; Park, Changwon; Smith, Craig S; Choi, Kyunghee; Long, Fanxin; Hui, Chi-chung; Ornitz, David M

    2006-06-15

    Myocardial infarction and ischemic heart disease are the leading cause of death in the industrial world. Therapies employed for treating these diseases are aimed at promoting increased blood flow to cardiac tissue. Pharmacological induction of new coronary growth has recently been explored, however, clinical trials with known proangiogenic factors have been disappointing. To identify novel therapeutic targets, we have explored signaling pathways that govern embryonic coronary development. Using a combination of genetically engineered mice and an organ culture system, we identified novel roles for fibroblast growth factor (FGF) and Hedgehog (HH) signaling in coronary vascular development. We show that FGF signals promote coronary growth indirectly by signaling to the cardiomyoblast through redundant function of Fgfr1 and Fgfr2. Myocardial FGF signaling triggers a wave of HH activation that is essential for vascular endothelial growth factor (Vegf)-A, Vegf-B, Vegf-C, and angiopoietin-2 (Ang2) expression. We demonstrate that HH is necessary for coronary vascular development and activation of HH signaling is sufficient to promote coronary growth and to rescue coronary defects due to loss of FGF signaling. These studies implicate HH signaling as an essential regulator of coronary vascular development and as a potential therapeutic target for coronary neovascularization. Consistent with this, activation of HH signaling in the adult heart leads to an increase in coronary vessel density. PMID:16778080

  19. TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis.

    PubMed

    Principe, Daniel R; DeCant, Brian; Mascariñas, Emman; Wayne, Elizabeth A; Diaz, Andrew M; Akagi, Naomi; Hwang, Rosa; Pasche, Boris; Dawson, David W; Fang, Deyu; Bentrem, David J; Munshi, Hidayatullah G; Jung, Barbara; Grippo, Paul J

    2016-05-01

    In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8(+) T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFβ may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFβ signals in the epithelium. Cancer Res; 76(9); 2525-39. ©2016 AACR. PMID:26980767

  20. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.

    PubMed

    Rankin, Erinn B; Fuh, Katherine C; Castellini, Laura; Viswanathan, Kartik; Finger, Elizabeth C; Diep, Anh N; LaGory, Edward L; Kariolis, Mihalis S; Chan, Andy; Lindgren, David; Axelson, Håkan; Miao, Yu R; Krieg, Adam J; Giaccia, Amato J

    2014-09-16

    Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma. PMID:25187556

  1. Coordinated niche-associated signals promote germline homeostasis in the Drosophila ovary

    PubMed Central

    Liu, Zhong; Zhong, Guohua; Chai, Phing Chian; Luo, Lichao; Liu, Sen; Yang, Ying; Baeg, Gyeong-Hun

    2015-01-01

    Stem cell niches provide localized signaling molecules to promote stem cell fate and to suppress differentiation. The Drosophila melanogaster ovarian niche is established by several types of stromal cells, including terminal filament cells, cap cells, and escort cells (ECs). Here, we show that, in addition to its well-known function as a niche factor expressed in cap cells, the Drosophila transforming growth factor β molecule Decapentaplegic (Dpp) is expressed at a low level in ECs to maintain a pool of partially differentiated germline cells that may dedifferentiate to replenish germline stem cells upon their depletion under normal and stress conditions. Our study further reveals that the Dpp level in ECs is modulated by Hedgehog (Hh) ligands, which originate from both cap cells and ECs. We also demonstrate that Hh signaling exerts its function by suppressing Janus kinase/signal transducer activity, which promotes Dpp expression in ECs. Collectively, our data suggest a complex interplay of niche-associated signals that controls the development of a stem cell lineage. PMID:26504174

  2. Multiple effects of Bacillus amyloliquefaciens volatile compounds: plant growth promotion and growth inhibition of phytopathogens.

    PubMed

    Asari, Shashidar; Matzén, Staffan; Petersen, Mikael Agerlin; Bejai, Sarosh; Meijer, Johan

    2016-06-01

    Biotic interactions through volatile organic compounds (VOC) are frequent in nature. This investigation aimed to study the role of ITALIC! BacillusVOC for the beneficial effects on plants observed as improved growth and pathogen control. Four ITALIC! Bacillus amyloliquefacienssubsp. ITALIC! plantarumstrains were screened for VOC effects on ITALIC! Arabidopsis thalianaCol-0 seedlings and ITALIC! Brassicafungal phytopathogens. VOC from all four ITALIC! Bacillusstrains could promote growth of ITALIC! Arabidopsisplants resulting in increased shoot biomass but the effects were dependent on the growth medium. Dose response studies with UCMB5113 on MS agar with or without root exudates showed significant plant growth promotion even at low levels of bacteria. ITALIC! BacillusVOC antagonized growth of several fungal pathogens ITALIC! in vitro However, the plant growth promotion efficacy and fungal inhibition potency varied among the ITALIC! Bacillusstrains. VOC inhibition of several phytopathogens indicated efficient microbial antagonism supporting high rhizosphere competence of the ITALIC! Bacillusstrains. GC-MS analysis identified several VOC structures where the profiles differed depending on the growth medium. The ability of ITALIC! Bacillusstrains to produce both volatile and soluble compounds for plant growth promotion and disease biocontrol provides examples of rhizosphere microbes as an important ecosystem service with high potential to support sustainable crop production. PMID:27053756

  3. Plant growth promotion induced by phosphate solubilizing endophytic Pseudomonas isolates

    PubMed Central

    Oteino, Nicholas; Lally, Richard D.; Kiwanuka, Samuel; Lloyd, Andrew; Ryan, David; Germaine, Kieran J.; Dowling, David N.

    2015-01-01

    The use of plant growth promoting bacterial inoculants as live microbial biofertilizers provides a promising alternative to chemical fertilizers and pesticides. Inorganic phosphate solubilization is one of the major mechanisms of plant growth promotion by plant associated bacteria. This involves bacteria releasing organic acids into the soil which solubilize the phosphate complexes converting them into ortho-phosphate which is available for plant up-take and utilization. The study presented here describes the ability of endophytic bacteria to produce gluconic acid (GA), solubilize insoluble phosphate, and stimulate the growth of Pisum sativum L. plants. This study also describes the genetic systems within three of these endophyte strains thought to be responsible for their effective phosphate solubilizing abilities. The results showed that many of the endophytic strains produced GA (14–169 mM) and have moderate to high phosphate solubilization capacities (~400–1300 mg L−1). When inoculated into P. sativum L. plants grown in soil under soluble phosphate limiting conditions, the endophytes that produced medium-high levels of GA displayed beneficial plant growth promotion effects. PMID:26257721

  4. Growth promoting effects of some lichen metabolites on probiotic bacteria.

    PubMed

    Gaikwad, Subhash; Verma, Neeraj; Sharma, B O; Behera, B C

    2014-10-01

    In the present study, the extract of four natural lichen species Canoparmelia eruptens, Everniastrum cirrhatum, Parmotrema austrosinense and Rimelia cetrata were studied for the source of natural antioxidant and their purified secondary metabolites were evaluated for growth promoting effects on probiotic bacteria Lactobacillus casei. The methanolic fraction of lichen species showed moderate to high antioxidant activity in the order P. austrosinense > E. cirrhatum > C. eruptens > R. cetrata. The lichen metabolites showed antioxidant activity with an IC50 values (μg/ml); lecanoric acid 79-95, salazinic 88-108, atranorin 100-116 and consalazinic acid 119-125. As far as the growth promoting effects of lichen metabolites on L. casei is concerned, lecanoric acid at 100 μg/ml conc. showed high growth stimulating activity in terms of increased dry matter of biomass (56.08 mg) of L. casei. Other lichen metabolites; salazinic acid, atranorin and consalazinic acid produced relatively less dry biomass 43.98 mg, 41.1 mg, 40.68 mg, respectively. However, standard antioxidants butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and Trolox after 36 h produced 39.04-47.81 mg dry biomass. At lower pH the growth promoting activity of lichen metabolites was found stable. PMID:25328204

  5. Exendin-4 promotes proliferation of adipose-derived stem cells through ERK and JNK signaling pathways.

    PubMed

    Zhang, Ying; Chen, Shi; Liu, Baichuan; Zhou, Hao; Hu, Shunyin; Zhou, Ying; Han, Tianwen; Chen, Yundai

    2016-05-01

    Adipose-derived stem cell (ADSC) transplantation has emerged as a potential tool for the treatment of cardiovascular disease. However, with a limited renewal capacity and the need for mass cells during the engraftment, strategies are needed to enhance ADSC proliferative capacity. In this study, we explored the effects of exendin-4 (Ex-4), a glucagon-like peptide-1 analog, on the growth of ADSCs, focusing in particular on c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways. Firstly, ADSCs were isolated and cultured in vitro. Then, flow cytometry demonstrated that ADSCs were positive for CD90 and CD29 but negative for CD31, CD34, and CD45. Ex-4 (0-50 nM) treatment increased ADSC proliferation in a dose-dependent manner but had no effects on stem cell markers of ADSCs. Moreover, we found that Ex-4 treatment elevated the phosphorylation levels of the JNK and ERK signaling pathways. Furthermore, utilization of Ex-4 also promoted cyclin D1 and cyclin E protein expression, which was accompanied by more Edu(+) cells and a higher percentage of cells in the S-phase of the cell cycle after Ex-4 treatment. In parallel, the application of inhibitors SP600125 and PD98059, inhibitors of the JNK and ERK signaling pathways, respectively, not only reversed such effects of Ex-4 on JNK and ERK but also resulted in lower percentages of S-phase cells and fewer numbers of Edu(+) cells. In summary, Ex-4 has no effects on stem cell markers in ADSCs but promotes ADSC growth via JNK and ERK signaling pathways. PMID:26932601

  6. Plant growth promoting bacteria from Crocus sativus rhizosphere.

    PubMed

    Ambardar, Sheetal; Vakhlu, Jyoti

    2013-12-01

    Present study deals with the isolation of rhizobacteria and selection of plant growth promoting bacteria from Crocus sativus (Saffron) rhizosphere during its flowering period (October-November). Bacterial load was compared between rhizosphere and bulk soil by counting CFU/gm of roots and soil respectively, and was found to be ~40 times more in rhizosphere. In total 100 bacterial isolates were selected randomly from rhizosphere and bulk soil (50 each) and screened for in-vitro and in vivo plant growth promoting properties. The randomly isolated bacteria were identified by microscopy, biochemical tests and sequence homology of V1-V3 region of 16S rRNA gene. Polyphasic identification categorized Saffron rhizobacteria and bulk soil bacteria into sixteen different bacterial species with Bacillus aryabhattai (WRF5-rhizosphere; WBF3, WBF4A and WBF4B-bulk soil) common to both rhizosphere as well as bulk soil. Pseudomonas sp. in rhizosphere and Bacillus and Brevibacterium sp. in the bulk soil were the predominant genera respectively. The isolated rhizobacteria were screened for plant growth promotion activity like phosphate solubilization, siderophore and indole acetic acid production. 50 % produced siderophore and 33 % were able to solubilize phosphate whereas all the rhizobacterial isolates produced indole acetic acid. The six potential PGPR showing in vitro activities were used in pot trial to check their efficacy in vivo. These bacteria consortia demonstrated in vivo PGP activity and can be used as PGPR in Saffron as biofertilizers.This is the first report on the isolation of rhizobacteria from the Saffron rhizosphere, screening for plant growth promoting bacteria and their effect on the growth of Saffron plant. PMID:23749248

  7. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    SciTech Connect

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A.; Gallardo-Escarate, C.; Molina, A.; Valdés, J.A.

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  8. Red ginseng extract promotes the hair growth in cultured human hair follicles.

    PubMed

    Park, Gyeong-Hun; Park, Ki-young; Cho, Hong-il; Lee, Sang-Min; Han, Ji Su; Won, Chong Hyun; Chang, Sung Eun; Lee, Mi Woo; Choi, Jee Ho; Moon, Kee Chan; Shin, Hyoseung; Kang, Yong Jung; Lee, Dong Hun

    2015-03-01

    Ginseng has been shown to promote hair growth in several recent studies. However, its effects on human hair follicles and its mechanisms of action have not been sufficiently elucidated. This study aimed to investigate the hair growth-promoting effects of red ginseng extract (RGE) and its ginsenosides. The proliferative activities of cultured human hair follicles treated with RGE and ginsenoside-Rb1 were assessed using Ki-67 immunostaining. Their effects on isolated human dermal papilla cells (hDPCs) were evaluated using cytotoxicity assays, immunoblot analysis of signaling proteins, and the determination of associated growth factors. We examined the ability of RGE and ginsenosides to protect hair matrix keratinocyte proliferation against dihydrotestosterone (DHT)-induced suppression and their effects on the expression of androgen receptor. The in vivo hair growth-promoting effect of RGE was also investigated in C57BL/6 mice. Both RGE and ginsenoside-Rb1 enhanced the proliferation of hair matrix keratinocytes. hDPCs treated with RGE or ginsenoside-Rb1 exhibited substantial cell proliferation and the associated phosphorylation of ERK and AKT. Moreover, RGE, ginsenoside-Rb1, and ginsenoside-Rg3 abrogated the DHT-induced suppression of hair matrix keratinocyte proliferation and the DHT-induced upregulation of the mRNA expression of androgen receptor in hDPCs. Murine experiments revealed that the subcutaneous injection of 3% RGE resulted in more rapid hair growth than the negative control. In conclusion, RGE and its ginsenosides may enhance hDPC proliferation, activate ERK and AKT signaling pathways in hDPCs, upregulate hair matrix keratinocyte proliferation, and inhibit the DHT-induced androgen receptor transcription. These results suggest that red ginseng may promote hair growth in humans. PMID:25396716

  9. Red Ginseng Extract Promotes the Hair Growth in Cultured Human Hair Follicles

    PubMed Central

    Park, Gyeong-Hun; Park, Ki-young; Cho, Hong-il; Lee, Sang-Min; Han, Ji Su; Chang, Sung Eun; Lee, Mi Woo; Choi, Jee Ho; Moon, Kee Chan; Shin, Hyoseung; Kang, Yong Jung; Lee, Dong Hun

    2015-01-01

    Abstract Ginseng has been shown to promote hair growth in several recent studies. However, its effects on human hair follicles and its mechanisms of action have not been sufficiently elucidated. This study aimed to investigate the hair growth-promoting effects of red ginseng extract (RGE) and its ginsenosides. The proliferative activities of cultured human hair follicles treated with RGE and ginsenoside-Rb1 were assessed using Ki-67 immunostaining. Their effects on isolated human dermal papilla cells (hDPCs) were evaluated using cytotoxicity assays, immunoblot analysis of signaling proteins, and the determination of associated growth factors. We examined the ability of RGE and ginsenosides to protect hair matrix keratinocyte proliferation against dihydrotestosterone (DHT)-induced suppression and their effects on the expression of androgen receptor. The in vivo hair growth-promoting effect of RGE was also investigated in C57BL/6 mice. Both RGE and ginsenoside-Rb1 enhanced the proliferation of hair matrix keratinocytes. hDPCs treated with RGE or ginsenoside-Rb1 exhibited substantial cell proliferation and the associated phosphorylation of ERK and AKT. Moreover, RGE, ginsenoside-Rb1, and ginsenoside-Rg3 abrogated the DHT-induced suppression of hair matrix keratinocyte proliferation and the DHT-induced upregulation of the mRNA expression of androgen receptor in hDPCs. Murine experiments revealed that the subcutaneous injection of 3% RGE resulted in more rapid hair growth than the negative control. In conclusion, RGE and its ginsenosides may enhance hDPC proliferation, activate ERK and AKT signaling pathways in hDPCs, upregulate hair matrix keratinocyte proliferation, and inhibit the DHT-induced androgen receptor transcription. These results suggest that red ginseng may promote hair growth in humans. PMID:25396716

  10. Siderophores from Neighboring Organisms Promote the Growth of Uncultured Bacteria

    PubMed Central

    D’Onofrio, Anthony; Crawford, Jason M.; Stewart, Eric J.; Witt, Kathrin; Gavrish, Ekaterina; Epstein, Slava; Clardy, Jon; Lewis, Kim

    2010-01-01

    Summary The majority of bacterial species do not grow on synthetic media. Many non-growers require growth factors from other bacteria, but the nature of these compounds is largely unknown. We show here that previously uncultured isolates from marine sediment biofilm grow on a Petri dish in the presence of cultured organisms from the same environment. The growth factors produced by one cultured helper strain were identified as new acyl-desferrioxamine siderophores. A panel of previously uncultured isolates exhibited a range of siderophore promiscuity for growth promotion. This siderophore-based approach has enabled the culturing of organisms only distantly related to previously cultured microbes. The lack of growth in the lab for many strains from this habitat stems from an inability to autonomously produce siderophores, and the resulting chemical dependence on other microorganisms regulates community establishment in the environment. PMID:20338517

  11. The Tetraspanin CD151 Is Required for Met-dependent Signaling and Tumor Cell Growth*

    PubMed Central

    Franco, Mélanie; Muratori, Claudia; Corso, Simona; Tenaglia, Enrico; Bertotti, Andrea; Capparuccia, Lorena; Trusolino, Livio; Comoglio, Paolo M.; Tamagnone, Luca

    2010-01-01

    CD151, a transmembrane protein of the tetraspanin family, is implicated in the regulation of cell-substrate adhesion and cell migration through physical and functional interactions with integrin receptors. In contrast, little is known about the potential role of CD151 in controlling cell proliferation and survival. We have previously shown that β4 integrin, a major CD151 partner, not only acts as an adhesive receptor for laminins but also as an intracellular signaling platform promoting cell proliferation and invasive growth upon interaction with Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF). Here we show that RNAi-mediated silencing of CD151 expression in cancer cells impairs HGF-driven proliferation, anchorage-independent growth, protection from anoikis, and tumor progression in xenograft models in vivo. Mechanistically, we found that CD151 is crucially implicated in the formation of signaling complexes between Met and β4 integrin, a known amplifier of HGF-induced tumor cell growth and survival. CD151 depletion hampered HGF-induced phosphorylation of β4 integrin and the ensuing Grb2-Gab1 association, a signaling pathway leading to MAPK stimulation and cell growth. Accordingly, CD151 knockdown reduced HGF-triggered activation of MAPK but not AKT signaling cascade. These results indicate that CD151 controls Met-dependent neoplastic growth by enhancing receptor signaling through β4 integrin-mediated pathways, independent of cell-substrate adhesion. PMID:20937830

  12. Drosophila Spidey/Kar Regulates Oenocyte Growth via PI3-Kinase Signaling

    PubMed Central

    Cinnamon, Einat; Sawala, Annick; Tittiger, Claus; Paroush, Ze'ev

    2016-01-01

    Cell growth and proliferation depend upon many different aspects of lipid metabolism. One key signaling pathway that is utilized in many different anabolic contexts involves Phosphatidylinositide 3-kinase (PI3K) and its membrane lipid products, the Phosphatidylinositol (3,4,5)-trisphosphates. It remains unclear, however, which other branches of lipid metabolism interact with the PI3K signaling pathway. Here, we focus on specialized fat metabolizing cells in Drosophila called larval oenocytes. In the presence of dietary nutrients, oenocytes undergo PI3K-dependent cell growth and contain very few lipid droplets. In contrast, during starvation, oenocytes decrease PI3K signaling, shut down cell growth and accumulate abundant lipid droplets. We now show that PI3K in larval oenocytes, but not in fat body cells, functions to suppress lipid droplet accumulation. Several enzymes of fatty acid, triglyceride and hydrocarbon metabolism are required in oenocytes primarily for lipid droplet induction rather than for cell growth. In contrast, a very long chain fatty-acyl-CoA reductase (FarO) and a putative lipid dehydrogenase/reductase (Spidey, also known as Kar) not only promote lipid droplet induction but also inhibit oenocyte growth. In the case of Spidey/Kar, we show that the growth suppression mechanism involves inhibition of the PI3K signaling pathway upstream of Akt activity. Together, the findings in this study show how Spidey/Kar and FarO regulate the balance between the cell growth and lipid storage of larval oenocytes. PMID:27500738

  13. Drosophila Spidey/Kar Regulates Oenocyte Growth via PI3-Kinase Signaling.

    PubMed

    Cinnamon, Einat; Makki, Rami; Sawala, Annick; Wickenberg, Leah P; Blomquist, Gary J; Tittiger, Claus; Paroush, Ze'ev; Gould, Alex P

    2016-08-01

    Cell growth and proliferation depend upon many different aspects of lipid metabolism. One key signaling pathway that is utilized in many different anabolic contexts involves Phosphatidylinositide 3-kinase (PI3K) and its membrane lipid products, the Phosphatidylinositol (3,4,5)-trisphosphates. It remains unclear, however, which other branches of lipid metabolism interact with the PI3K signaling pathway. Here, we focus on specialized fat metabolizing cells in Drosophila called larval oenocytes. In the presence of dietary nutrients, oenocytes undergo PI3K-dependent cell growth and contain very few lipid droplets. In contrast, during starvation, oenocytes decrease PI3K signaling, shut down cell growth and accumulate abundant lipid droplets. We now show that PI3K in larval oenocytes, but not in fat body cells, functions to suppress lipid droplet accumulation. Several enzymes of fatty acid, triglyceride and hydrocarbon metabolism are required in oenocytes primarily for lipid droplet induction rather than for cell growth. In contrast, a very long chain fatty-acyl-CoA reductase (FarO) and a putative lipid dehydrogenase/reductase (Spidey, also known as Kar) not only promote lipid droplet induction but also inhibit oenocyte growth. In the case of Spidey/Kar, we show that the growth suppression mechanism involves inhibition of the PI3K signaling pathway upstream of Akt activity. Together, the findings in this study show how Spidey/Kar and FarO regulate the balance between the cell growth and lipid storage of larval oenocytes. PMID:27500738

  14. Plant growth promotion traits of phosphobacteria isolated from Puna, Argentina.

    PubMed

    Viruel, Emilce; Lucca, María E; Siñeriz, Faustino

    2011-07-01

    The ability of soil microorganisms to solubilize phosphate is an important trait of plant growth-promoting bacteria leading to increased yields and smaller use of fertilizers. This study presents the isolation and characterization of phosphobacteria from Puna, northwestern Argentina and the ability to produce phosphate solubilization, alkaline phosphatase, siderophores, and indole acetic acid. The P-solubilizing activity was coincidental with a decrease in pH values of the tricalcium phosphate medium for all strains after 72 h of incubation. All the isolates showed the capacity to produce siderophores and indoles. Identification by 16S rDNA sequencing and phylogenetic analysis revealed that these strains belong to the genera Pantoea, Serratia, Enterobacter, and Pseudomonas. These isolates appear attractive for exploring their plant growth-promoting activity and potential field application. PMID:21442320

  15. Material and method for promoting the growth of anaerobic bacteria

    DOEpatents

    Adler, H.I.

    1984-10-09

    A material and method is disclosed for promoting the growth of anaerobic bacteria which includes a nutrient media containing a hydrogen donor and sterile membrane fragments of bacteria having an electron transfer system which reduces oxygen to water. Dissolved oxygen in the medium is removed by adding the sterile membrane fragments to the nutrient medium and holding the medium at a temperature of about 10 to about 60 C until the dissolved oxygen is removed. No Drawings

  16. Material and method for promoting the growth of anaerobic bacteria

    DOEpatents

    Adler, Howard I.

    1984-01-01

    A material and method for promoting the growth of anaerobic bacteria which includes a nutrient media containing a hydrogen donor and sterile membrane fragments of bacteria having an electron transfer system which reduces oxygen to water. Dissolved oxygen in the medium is removed by adding the sterile membrane fragments to the nutrient medium and holding the medium at a temperature of about 10.degree. to about 60.degree. C. until the dissolved oxygen is removed.

  17. Metabolic pathways promoting cancer cell survival and growth

    PubMed Central

    Boroughs, Lindsey K.; DeBerardinis, Ralph J.

    2016-01-01

    Activation of oncogenes and loss of tumour suppressors promote metabolic reprogramming in cancer, resulting in enhanced nutrient uptake to supply energetic and biosynthetic pathways. However, nutrient limitations within solid tumours may require that malignant cells exhibit metabolic flexibility to sustain growth and survival. Here, we highlight these adaptive mechanisms and also discuss emerging approaches to probe tumour metabolism in vivo and their potential to expand the metabolic repertoire of malignant cells even further. PMID:25774832

  18. Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

    PubMed Central

    Li, Wei; Gigante, Alba; Perez-Perez, Maria-Jesus; Yue, Hong; Hirano, Michio; McIntyre, Thomas; Silverstein, Roy L

    2014-01-01

    Rationale Platelets contain abundant thymidine phosphorylase (TYMP), which is highly expressed in diseases with high risk of thrombosis, such as atherosclerosis and type II diabetes. Objective Test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis. Methods and Results By using a ferric chloride (FeCl3) induced carotid artery injury thrombosis model, we found time to blood flow cessation was significantly prolonged in Tymp−/− and Tymp+/− mice compared to wild type (WT) mice. Bone marrow transplantation and platelet transfusion studies demonstrated that platelet TYMP was responsible for the antithrombotic phenomenon in the TYMP deficient mice. Collagen-, collagen-related peptide (CRP)-, adenosine diphosphate-and/or thrombin-induced platelet aggregation were significantly attenuated in Tymp+/− and Tymp−/− platelets, and in WT or human platelets pretreated with TYMP inhibitor KIN59. Tymp deficiency also significantly decreased agonist-induced P-select in expression. TYMP contains an N-terminal SH3 domain binding proline-rich motif and forms a complex with the tyrosine kinases Lyn, Fyn and Yes in platelets. TYMP-associated Lyn was inactive in resting platelets, and TYMP trapped and diminished active Lyn after collagen stimulation. Tymp/Lyn double haploinsufficiency diminished the antithrombotic phenotype of Tymp+/− mice. TYMP deletion or inhibition of TYMP with KIN59 dramatically increased PECAM-1 tyrosine phosphorylation and diminished CRP or collagen induced AKT phosphorylation. In vivo administration of KIN59 significantly inhibited FeCl3 induced carotid artery thrombosis without affecting hemostasis. Conclusion TYMP participates in multiple platelet signaling pathways and regulates platelet activation and thrombosis. Targeting TYMP might be a novel anti-platelet and anti-thrombosis therapy. PMID:25287063

  19. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling

    SciTech Connect

    Yonezawa, Takayuki; Lee, Ji-Won; Hibino, Ayaka; Asai, Midori; Hojo, Hironori; Cha, Byung-Yoon; Teruya, Toshiaki; Nagai, Kazuo; Chung, Ung-Il; Yagasaki, Kazumi; and others

    2011-06-03

    Highlights: {yields} Harmine promotes the activity and mRNA expression of ALP. {yields} Harmine enhances the expressions of osteocalcin mRNA and protein. {yields} Harmine induces osteoblastic mineralization. {yields} Harmine upregulates the mRNA expressions of BMPs, Runx2 and Osterix. {yields} BMP signaling pathways are involved in the actions of harmine. -- Abstract: Bone mass is regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. We previously reported that harmine, a {beta}-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo. In this study, we investigated the effects of harmine on osteoblast proliferation, differentiation and mineralization. Harmine promoted alkaline phosphatase (ALP) activity in MC3T3-E1 cells without affecting their proliferation. Harmine also increased the mRNA expressions of the osteoblast marker genes ALP and Osteocalcin. Furthermore, the mineralization of MC3T3-E1 cells was enhanced by treatment with harmine. Harmine also induced osteoblast differentiation in primary calvarial osteoblasts and mesenchymal stem cell line C3H10T1/2 cells. Structure-activity relationship studies using harmine-related {beta}-carboline alkaloids revealed that the C3-C4 double bond and 7-hydroxy or 7-methoxy group of harmine were important for its osteogenic activity. The bone morphogenetic protein (BMP) antagonist noggin and its receptor kinase inhibitors dorsomorphin and LDN-193189 attenuated harmine-promoted ALP activity. In addition, harmine increased the mRNA expressions of Bmp-2, Bmp-4, Bmp-6, Bmp-7 and its target gene Id1. Harmine also enhanced the mRNA expressions of Runx2 and Osterix, which are key transcription factors in osteoblast differentiation. Furthermore, BMP-responsive and Runx2-responsive reporters were activated by harmine treatment. Taken together, these results indicate that harmine enhances osteoblast differentiation probably by inducing the expressions of

  20. Progranulin promotes colorectal cancer proliferation and angiogenesis through TNFR2/Akt and ERK signaling pathways

    PubMed Central

    Yang, Dong; Wang, Lin-Lin; Dong, Tao-Tao; Shen, Yi-Hang; Guo, Xiao-Sun; Liu, Chuan-Yong; Liu, Jie; Zhang, Pei; Li, Juan; Sun, Yu-Ping

    2015-01-01

    Progranulin (PGRN) has been shown to be involved in the process of inflammation, wound healing, and cartilage development; and its role in the progression of breast and ovarian cancer is also well established. However, the expression status of PGRN in colorectal cancers (CRCs) and its molecular mechanisms responsible for tumorigenesis have not been addressed so far. Herein, we demonstrated that PGRN was highly expressed and had clinical relevance with CRCs since its overexpression was associated with advanced stages of CRCs, poorer patients’ prognosis, and increased expression of proliferation and angiogenesis markers. PGRN up-regulation significantly promoted the expression of Ki67 and vascular endothelial growth factor A (VEGF-A) as well as the growth rate in CRC cell lines, while PGRN down-regulation had the opposite effects. Strikingly, PGRN derived from CRCs could directly induce proliferation, migration, tubule formation, as well as VEGF-A expression in human umbilical vein endothelial cells (HUVECs). Furthermore, we provided mechanistic evidences that the regulation of Ki67 and VEGF-A expression by PGRN was mediated by tumor necrosis factor receptor 2 (TNFR2)/Akt and the ERK signaling pathways in both CRC cells and HUVECs. Taken together, these findings suggested that PGRN could promote proliferation and angiogenesis through TNFR2/Akt and ERK signaling pathways in CRCs, providing the new insight into the mechanism of PGRN in tumor proliferation and angiogenesis. PMID:26693061

  1. Promotion

    PubMed Central

    Alam, Hasan B.

    2013-01-01

    This article gives an overview of the promotion process in an academic medical center. A description of different promotional tracks, tenure and endowed chairs, and the process of submitting an application is provided. Finally, some practical advice about developing skills and attributes that can help with academic growth and promotion is dispensed. PMID:24436683

  2. Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

    PubMed Central

    Liu, Runping; Zhao, Renping; Zhou, Xiqiao; Liang, Xiuyin; Campbell, Deanna JW; Zhang, Xiaoxuan; Zhang, Luyong; Shi, Ruihua; Wang, Guangji; Pandak, William M; Sirica, Alphonse E; Hylemon, Phillip B; Zhou, Huiping

    2014-01-01

    Cholangiocarcinoma (CCA) is an often fatal primary malignancy of the intra- and extrahepatic biliary tract that is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids (CBAs), which are correlated with bile duct obstruction (BDO). BDO has also recently been shown to promote CCA progression. However, whereas there is increasing evidence linking chronic cholestasis and abnormal bile acid profiles to CCA development and progression, the specific mechanisms by which bile acids may be acting to promote cholangiocarcinogenesis and invasive biliary tumor growth have not been fully established. Recent studies have shown that CBAs, but not free bile acids, stimulate CCA cell growth, and that an imbalance in the ratio of free to CBAs may play an important role in the tumorigenesis of CCA. Also, CBAs are able to activate extracellular signal-regulated kinase (ERK)1/2- and phosphatidylinositol-3-kinase/protein kinase B (AKT)-signaling pathways through sphingosine 1-phosphate receptor 2 (S1PR2) in rodent hepatocytes. In the current study, we demonstrate S1PR2 to be highly expressed in rat and human CCA cells, as well as in human CCA tissues. We further show that CBAs activate the ERK1/2- and AKT-signaling pathways and significantly stimulate CCA cell growth and invasion in vitro. Taurocholate (TCA)-mediated CCA cell proliferation, migration, and invasion were significantly inhibited by JTE-013, a chemical antagonist of S1PR2, or by lentiviral short hairpin RNA silencing of S1PR2. In a novel organotypic rat CCA coculture model, TCA was further found to significantly increase the growth of CCA cell spheroidal/“duct-like” structures, which was blocked by treatment with JTE-013. Conclusion: Our collective data support the hypothesis that CBAs promote CCA cell-invasive growth through S1PR2. PMID:24700501

  3. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors

    PubMed Central

    Wu, Jianqiang; Patmore, Deanna M.; Jousma, Edwin; Eaves, David W.; Breving, Kimberly; Patel, Ami V.; Schwartz, Eric B.; Fuchs, James R.; Cripe, Timothy P.; Stemmer-Rachamimov, Anat O.; Ratner, Nancy

    2014-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1 (NF1). EGFR overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics. PMID:23318430

  4. Soil bacteria as sources of virulence signal providers promoting plant infection by Phytophthora pathogens.

    PubMed

    Kong, Ping; Hong, Chuanxue

    2016-01-01

    Phytophthora species are known as "plant destroyers" capable of initiating single zoospore infection in the presence of a quorum of chemical signals from the same or closely related species of oomycetes. Since the natural oomycete population is too low to reach a quorum necessary to initiate a disease epidemic, creation of the quorum is reliant on alternate sources. Here, we show that a soil bacterial isolate, Bacillus megaterium Sb5, promotes plant infection by Phytophthora species. In the presence of Sb5 exudates, colonization of rhododendron leaf discs by 12 Phytophthora species/isolates was significantly enhanced, single zoospores of P. nicotianae infected annual vinca and P. sojae race 25 successfully attacked a non-host plant, Nicotiana benthamiana as well as resistant soybean cultivars with RPS1a or RPS3a. Sb5 exudates, most notably the fractions larger than 3 kDa, promoted plant infection by improving zoospore swimming, germination and plant attachment. Sb5 exudates also stimulated infection hypha growth and upregulated effector gene expression. These results suggest that environmental bacteria are important sources of virulence signal providers that promote plant infection by Phytophthora species, advancing our understanding of biotic factors in the environmental component of the Phytophthora disease triangle and of communal infection of plant pathogens. PMID:27616267

  5. Bile signalling promotes chronic respiratory infections and antibiotic tolerance

    PubMed Central

    Reen, F. Jerry; Flynn, Stephanie; Woods, David F.; Dunphy, Niall; Chróinín, Muireann Ní; Mullane, David; Stick, Stephen; Adams, Claire; O’Gara, Fergal

    2016-01-01

    Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease. PMID:27432520

  6. Bile signalling promotes chronic respiratory infections and antibiotic tolerance.

    PubMed

    Reen, F Jerry; Flynn, Stephanie; Woods, David F; Dunphy, Niall; Chróinín, Muireann Ní; Mullane, David; Stick, Stephen; Adams, Claire; O'Gara, Fergal

    2016-01-01

    Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease. PMID:27432520

  7. Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment.

    PubMed

    Saxon, Jamie A; Sherrill, Taylor P; Polosukhin, Vasiliy V; Sai, Jiqing; Zaynagetdinov, Rinat; McLoed, Allyson G; Gulleman, Peter M; Barham, Whitney; Cheng, Dong-Sheng; Hunt, Raphael P; Gleaves, Linda A; Richmond, Ann; Young, Lisa R; Yull, Fiona E; Blackwell, Timothy S

    2016-06-01

    Several studies have demonstrated that NF-κB activation is common in lung cancer; however, the mechanistic links between NF-κB signaling and tumorigenesis remain to be fully elucidated. We investigated the function of NF-κB signaling in epidermal growth factor receptor (EGFR)-mutant lung tumors using a transgenic mouse model with doxycycline (dox)-inducible expression of oncogenic EGFR in the lung epithelium with or without a dominant inhibitor of NF-κB signaling. NF-κB inhibition resulted in a significant reduction in tumor burden in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant tumors. However, NF-κB inhibition did not alter epithelial cell survival in vitro or in vivo, and no changes were detected in activation of EGFR downstream signaling pathways. Instead, we observed an influx of inflammatory cells (macrophages and neutrophils) in the lungs of mice with oncogenic EGFR expression that was blocked in the setting of NF-κB inhibition. To investigate whether inflammatory cells play a role in promoting EGFR-mutant lung tumors, we depleted macrophages and neutrophils during tumorigenesis and found that neutrophil depletion had no effect on tumor formation, but macrophage depletion caused a significant reduction in tumor burden. Together, these data suggest that epithelial NF-κB signaling supports carcinogenesis in a non-cell autonomous manner in EGFR-mutant tumors through recruitment of pro-tumorigenic macrophages. PMID:27471643

  8. HEF1, a Novel Target of Wnt Signaling, Promotes Colonic Cell Migration and Cancer Progression

    PubMed Central

    Li, Yingchun; Bavarva, Jasmin H.; Wang, Zemin; Guo, Jianhui; Qian, Chiping; Thibodeau, Stephen N.; Golemis, Erica A.; Liu, Wanguo

    2011-01-01

    Misregulation of the canonical Wnt/β-catenin pathway and aberrant activation of Wnt signaling target genes are common in colorectal cancer and contribute to cancer progression. Altered expression of HEF1 (Human Enhancer of Filamentation 1, also known as NEDD9 or Cas-L) has been implicated in progression of melanoma, breast, and colorectal cancer. However, the regulation of HEF1 and the role of HEF1 in colorectal cancer tumorigenesis are not fully understood. We here identify HEF1 as a novel Wnt signaling target. The expression of HEF1 was up-regulated by Wnt3a, β-catenin, and Dvl2 in a dose-dependent fashion, and was suppressed following β-catenin down-regulation by shRNA. In addition, elevated HEF1 mRNA and protein levels were observed in colorectal cancer cell lines and primary tumor tissues, as well as in the colon and adenoma polyps of Apcmin/+ mice. Moreover, HEF1 levels in human colorectal tumor tissues increased with the tumor grade. Chromatin immunoprecipitation (ChIP) assays and HEF1 promoter analyses revealed three functional TCF-binding sites in the promoter of HEF1 responsible for HEF1 induction by Wnt signaling. Ectopic expression of HEF1 increased cell proliferation and colony formation, while down-regulation of HEF1 in SW480 cells by shRNA had the opposite effects and inhibited the xenograft tumor growth. Furthermore, overexpression of HEF1 in SW480 cells promoted cell migration and invasion. Together, our results determined a novel role of HEF1 as a mediator of the canonical Wnt/β-catenin signaling pathway for cell proliferation, migration, and tumorigenesis, as well as an important player in colorectal tumorigenesis and progression. HEF1 may represent an attractive candidate for drug targeting in colorectal cancer. PMID:21317929

  9. Cytokinin production by plant growth promoting rhizobacteria and selected mutants.

    PubMed

    García de Salamone, I E; Hynes, R K; Nelson, L M

    2001-05-01

    One of the proposed mechanisms by which rhizobacteria enhance plant growth is through the production of plant growth regulators. Five plant growth promoting rhizobacterial (PGPR) strains produced the cytokinin dihydrozeatin riboside (DHZR) in pure culture. Cytokinin production by Pseudomonas fluorescens G20-18, a rifampicin-resistant mutant (RIF), and two TnphoA-derived mutants (CNT1, CNT2), with reduced capacity to synthesize cytokinins, was further characterized in pure culture using immunoassay and thin layer chromatography. G20-18 produced higher amounts of three cytokinins, isopentenyl adenosine (IPA), trans-zeatin ribose (ZR), and DHZR than the three mutants during stationary phase. IPA was the major metabolite produced, but the proportion of ZR and DHZR accumulated by CNT1 and CNT2 increased with time. No differences were observed between strain G20-18 and the mutants in the amounts of indole acetic acid synthesized, nor were gibberellins detected in supernatants of any of the strains. Addition of 10(-5) M adenine increased cytokinin production in 96- and 168-h cultures of strain G20-18 by approximately 67%. G20-18 and the mutants CNT1 and CNT2 may be useful for determination of the role of cytokinin production in plant growth promotion by PGPR. PMID:11400730

  10. Evaluation of hair growth promoting activity of Phyllanthus niruri

    PubMed Central

    Patel, Satish; Sharma, Vikas; S. Chauhan, Nagendra; Thakur, Mayank; Dixit, Vinod Kumar

    2015-01-01

    Objective: This study was designed to investigate the potential Phyllanthus niruri (P. niruri ) extracts in promotion of hair growth. Materials and Methods: Here, we studied the hair growth promoting activity of petroleum ether extract of P. niruri following its topical administration. Alopecia was induced in albino rats by subcutaneous administration of testosterone for 21 days. Evaluation of hair loss inhibition was done by concurrent administration of extract and monitoring parameters like follicular density, anagen/telogen (A/T) ratio and histological observation of animal skin sections. Finasteride solution was applied topically as standard. In vitro experiments were also performed to study the effect of extract on the activity of 5α-reductase enzyme Results: Groups treated with petroleum ether extract of plant showed hair re-growth as reflected by follicular density, A/T ratio and skin sections. Histopathology and morphologic observations of hair re-growth at shaved sites showed active follicular proliferation. In vitro experiments results showed inhibitory activity of petroleum ether extract on type-2 5α-reductase enzyme and an increase in the amount of testosterone with increasing concentrations. Conclusion: It could be concluded that petroleum ether extracts of P. niruri might be useful in the treatment of testosterone-induced alopecia in the experimental animal by inhibiting 5α-reductase enzyme. PMID:26693408

  11. Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin-Binding Protein Eps8

    PubMed Central

    Salinas, Patricia C.

    2015-01-01

    Upon arrival at their synaptic targets, axons slow down their growth and extensively remodel before the assembly of presynaptic boutons. Wnt proteins are target-derived secreted factors that promote axonal remodelling and synaptic assembly. In the developing spinal cord, Wnts secreted by motor neurons promote axonal remodelling of NT-3 responsive dorsal root ganglia neurons. Axon remodelling induced by Wnts is characterised by growth cone pausing and enlargement, processes that depend on the re-organisation of microtubules. However, the contribution of the actin cytoskeleton has remained unexplored. Here, we demonstrate that Wnt3a regulates the actin cytoskeleton by rapidly inducing F-actin accumulation in growth cones from rodent DRG neurons through the scaffold protein Dishevelled-1 (Dvl1) and the serine-threonine kinase Gsk3β. Importantly, these changes in actin cytoskeleton occurs before enlargement of the growth cones is evident. Time-lapse imaging shows that Wnt3a increases lamellar protrusion and filopodia velocity. In addition, pharmacological inhibition of actin assembly demonstrates that Wnt3a increases actin dynamics. Through a yeast-two hybrid screen, we identified the actin-binding protein Eps8 as a direct interactor of Dvl1, a scaffold protein crucial for the Wnt signalling pathway. Gain of function of Eps8 mimics Wnt-mediated axon remodelling, whereas Eps8 silencing blocks the axon remodelling activity of Wnt3a. Importantly, blockade of the Dvl1-Eps8 interaction completely abolishes Wnt3a-mediated axonal remodelling. These findings demonstrate a novel role for Wnt-Dvl1 signalling through Eps8 in the regulation of axonal remodeling. PMID:26252776

  12. GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression.

    PubMed

    Baumgart, Sandra; Chen, Nai-Ming; Zhang, Jin-San; Billadeau, Daniel D; Gaisina, Irina N; Kozikowski, Alan P; Singh, Shiv K; Fink, Daniel; Ströbel, Philipp; Klindt, Caroline; Zhang, Lizhi; Bamlet, William R; Koenig, Alexander; Hessmann, Elisabeth; Gress, Thomas M; Ellenrieder, Volker; Neesse, Albrecht

    2016-03-01

    We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3β (GSK-3β) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells (NFATc2) in pancreatic cancer. IHC, qPCR, immunoblotting, immunofluorescence microscopy, and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein-protein interactions and promoter regulation were analyzed by coimmunoprecipitation, DNA pulldown, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts, and a genetically engineered mouse model (GEMM). GSK-3β-dependent SP2 phosphorylation mediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3β-mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters, such as cyclin-dependent kinase-6, which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3β module inhibits proliferation and tumor growth and interferes with inflammation-induced pancreatic cancer progression in Kras(G12D) mice. In conclusion, we describe a novel mechanism by which GSK-3β fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer. Mol Cancer Ther; 15(3); 491-502. ©2016 AACR. PMID:26823495

  13. Ecdysone signaling opposes epidermal growth factor signaling in regulating cyst differentiation in the male gonad of Drosophila melanogaster.

    PubMed

    Qian, Yue; Dominado, Nicole; Zoller, Richard; Ng, Chun; Kudyba, Karl; Siddall, Nicole A; Hime, Gary R; Schulz, Cordula

    2014-10-15

    The development of stem cell daughters into the differentiated state normally requires a cascade of proliferation and differentiation steps that are typically regulated by external signals. The germline cells of most animals, in specific, are associated with somatic support cells and depend on them for normal development. In the male gonad of Drosophila melanogaster, germline cells are completely enclosed by cytoplasmic extensions of somatic cyst cells, and these cysts form a functional unit. Signaling from the germline to the cyst cells via the Epidermal Growth Factor Receptor (EGFR) is required for germline enclosure and has been proposed to provide a temporal signature promoting early steps of differentiation. A temperature-sensitive allele of the EGFR ligand Spitz (Spi) provides a powerful tool for probing the function of the EGRF pathway in this context and for identifying other pathways regulating cyst differentiation via genetic interaction studies. Using this tool, we show that signaling via the Ecdysone Receptor (EcR), a known regulator of developmental timing during larval and pupal development, opposes EGF signaling in testes. In spi mutant animals, reducing either Ecdysone synthesis or the expression of Ecdysone signal transducers or targets in the cyst cells resulted in a rescue of cyst formation and cyst differentiation. Despite of this striking effect in the spi mutant background and the expression of EcR signaling components within the cyst cells, activity of the EcR pathway appears to be dispensable in a wildtype background. We propose that EcR signaling modulates the effects of EGFR signaling by promoting an undifferentiated state in early stage cyst cells. PMID:25169192

  14. CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling.

    PubMed

    Zang, Mingde; Zhang, Yunqiang; Zhang, Baogui; Hu, Lei; Li, Jianfang; Fan, Zhiyuan; Wang, Hexiao; Su, Liping; Zhu, Zhenggang; Li, Chen; Yan, Chao; Gu, Qinlong; Liu, Bingya; Yan, Min

    2015-05-01

    CEACAM6 is a member of glycosylphosphatidylinositol-linked immunoglobulin superfamily that is implicated in a variety of human cancers. In our previous study, we reported that CEACAM6 was overexpressed in gastric cancer tissues and promoted cancer metastasis. The purpose of this study is to determine the role of CEACAM6 in tumor angiogenesis and mimicry formation. We found that overexpressed CEACAM6 promoted tubule formation dependent on HUVEC cells and vasculogenic mimicry formation of gastric cancer cells; opposing results were achieved in CEACAM6-silenced groups. Moreover, we found that mosaic vessels formed by HUVEC cells and gastric cancer cells were observed in vitro by 3D-culture assay. Overexpressed CEACAM6 in gastric cancer cells promoted tumor growth, VEGF expression and vasculogenic mimicry structures formation in vivo. In accordance with these observations, we found that phosphorylation of FAK and phosphorylation of paxillin were up-regulated in CEACAM6-overexpressing gastric cancer cells, and FAK inhibitor Y15 could reduce tubule and vasculogenic mimicry formation. These findings suggest that CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry formation via FAK signaling in gastric cancer and CEACAM6 may be a new target for cancer anti-vascular treatment. PMID:25703140

  15. PARD3 induces TAZ activation and cell growth by promoting LATS1 and PP1 interaction

    PubMed Central

    Lv, Xian-Bo; Liu, Chen-Ying; Wang, Zhen; Sun, Yi-Ping; Xiong, Yue; Lei, Qun-Ying; Guan, Kun-Liang

    2015-01-01

    The Hippo pathway plays a major role in organ size control, and its dysregulation contributes to tumorigenesis. The major downstream effectors of the Hippo pathway are the YAP/TAZ transcription co-activators, which are phosphorylated and inhibited by the Hippo pathway kinase LATS1/2. Here, we report a novel mechanism of TAZ regulation by the tight junction protein PARD3. PARD3 promotes the interaction between PP1A and LATS1 to induce LATS1 dephosphorylation and inactivation, therefore leading to dephosphorylation and activation of TAZ. The cytoplasmic, but not the tight junction complex associated, PARD3 is responsible for TAZ regulation. Our study indicates a potential molecular basis for cell growth-promoting function of PARD3 by modulating the Hippo pathway signaling in response to cell contact and cell polarity signals. PMID:26116754

  16. Nucleolin promotes TGF-β signaling initiation via TGF-β receptor I in glioblastoma.

    PubMed

    Lv, Shunzeng; Zhang, Jie; Han, Mingzhi; Wang, Weiping; Zhang, Ya; Zhuang, Dongxiao; Shi, Ranran; Bian, Ruixiang; Yao, Chengjun

    2015-01-01

    The transforming growth factor β (TGF-β) pathway plays a key role in oncogenesis of advanced cancers, involving the non-Smad and Smad pathways. Meanwhile, nucleolin on the cell surface has been also reported to affect activation of signaling pathways. However, the effect of cell surface nucleolin on TGF-β pathway in glioblastoma is not still understood. Here, using antibodies of nucleolin and TGF-β receptor I (TβR-I), we observed blocking of either nucleolin or TβR-I inhibited the phosphorylation of CrkL, Erk1/2, and Smad2. Using nucleolin siRNA, nucleolin knockdown was also identified to suppress the expression of p-CrkL, p-Erk1/2, and p-Smad2. Furthermore, immunoprecipitation revealed the interaction between cell surface nucleolin and TβR-I on the U87 cell membrane. In addition, U87 cell wound-healing, soft-agar and MTT assay also showed si-nucleolin could obviously impair wound closure (p < 0.001), colony formation (p < 0.001) and cell growth (p < 0.001). In conclusion, nucleolin promotes and regulates the TGF-β pathway by interacting with TβR-I and is required for initiation and activation of TGF-β signaling. Thus, nucleolin could be a key factor in glioblastoma pathogenesis and considered a therapeutic target, which may also mediate more signaling pathways. PMID:24682943

  17. Reck enables cerebrovascular development by promoting canonical Wnt signaling.

    PubMed

    Ulrich, Florian; Carretero-Ortega, Jorge; Menéndez, Javier; Narvaez, Carlos; Sun, Belinda; Lancaster, Eva; Pershad, Valerie; Trzaska, Sean; Véliz, Evelyn; Kamei, Makoto; Prendergast, Andrew; Kidd, Kameha R; Shaw, Kenna M; Castranova, Daniel A; Pham, Van N; Lo, Brigid D; Martin, Benjamin L; Raible, David W; Weinstein, Brant M; Torres-Vázquez, Jesús

    2016-01-01

    The cerebral vasculature provides the massive blood supply that the brain needs to grow and survive. By acquiring distinctive cellular and molecular characteristics it becomes the blood-brain barrier (BBB), a selectively permeable and protective interface between the brain and the peripheral circulation that maintains the extracellular milieu permissive for neuronal activity. Accordingly, there is great interest in uncovering the mechanisms that modulate the formation and differentiation of the brain vasculature. By performing a forward genetic screen in zebrafish we isolated no food for thought (nft (y72)), a recessive late-lethal mutant that lacks most of the intracerebral central arteries (CtAs), but not other brain blood vessels. We found that the cerebral vascularization deficit of nft (y72) mutants is caused by an inactivating lesion in reversion-inducing cysteine-rich protein with Kazal motifs [reck; also known as suppressor of tumorigenicity 15 protein (ST15)], which encodes a membrane-anchored tumor suppressor glycoprotein. Our findings highlight Reck as a novel and pivotal modulator of the canonical Wnt signaling pathway that acts in endothelial cells to enable intracerebral vascularization and proper expression of molecular markers associated with BBB formation. Additional studies with cultured endothelial cells suggest that, in other contexts, Reck impacts vascular biology via the vascular endothelial growth factor (VEGF) cascade. Together, our findings have broad implications for both vascular and cancer biology. PMID:26657775

  18. SRPK2 promotes the growth and migration of the colon cancer cells.

    PubMed

    Wang, Jian; Wu, Hai-Feng; Shen, Wei; Xu, Dong-Yan; Ruan, Ting-Yan; Tao, Guo-Qing; Lu, Pei-Hua

    2016-07-15

    Colon cancer is one of the major causes of cancer-related death in the world. Understanding the molecular mechanism underlying this malignancy will facilitate the diagnosis and treatment. Serine-arginine protein kinase 2 (SRPK2) has been reported to be upregulated in several cancer types. However, its expression and functions in colon cancer remains unknown. In this study, it was found that the expression of SRPK2 was up-regulated in the clinical colon cancer samples. Overexpression of SRPK2 promoted the growth and migration of colon cancer cells, while knocking down the expression of SRPK2 inhibited the growth, migration and tumorigenecity of colon cancer cells. Molecular mechanism studies revealed that SRPK2 activated ERK signaling in colon cancer cells. Taken together, our study demonstrated the tumor promoting roles of SRPK2 in colon cancer cells and SRPK2 might be a promising therapeutic target for colon cancer. PMID:27041240

  19. Fusarium Oxysporum Volatiles Enhance Plant Growth Via Affecting Auxin Transport and Signaling

    PubMed Central

    Bitas, Vasileios; McCartney, Nathaniel; Li, Ningxiao; Demers, Jill; Kim, Jung-Eun; Kim, Hye-Seon; Brown, Kathleen M.; Kang, Seogchan

    2015-01-01

    Volatile organic compounds (VOCs) have well-documented roles in plant-plant communication and directing animal behavior. In this study, we examine the less understood roles of VOCs in plant-fungal relationships. Phylogenetically and ecologically diverse strains of Fusarium oxysporum, a fungal species complex that often resides in the rhizosphere of assorted plants, produce volatile compounds that augment shoot and root growth of Arabidopsis thaliana and tobacco. Growth responses of A. thaliana hormone signaling mutants and expression patterns of a GUS reporter gene under the auxin-responsive DR5 promoter supported the involvement of auxin signaling in F. oxysporum volatile-mediated growth enhancement. In addition, 1-naphthylthalamic acid, an inhibitor of auxin efflux, negated F. oxysporum volatile-mediated growth enhancement in both plants. Comparison of the profiles of volatile compounds produced by F. oxysporum strains that differentially affected plant growth suggests that the relative compositions of both growth inhibitory and stimulatory compounds may determine the degree of plant growth enhancement. Volatile-mediated signaling between fungi and plants may represent a potentially conserved, yet mostly overlooked, mechanism underpinning plant-fungus interactions and fungal niche adaption. PMID:26617587

  20. Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways

    PubMed Central

    Lawlor, Margaret A.; Feng, Xiuhong; Everding, Daniel R.; Sieger, Kerry; Stewart, Claire E. H.; Rotwein, Peter

    2000-01-01

    In addition to their ability to stimulate cell proliferation, polypeptide growth factors are able to maintain cell survival under conditions that otherwise lead to apoptotic death. Growth factors control cell viability through regulation of critical intracellular signal transduction pathways. We previously characterized C2 muscle cell lines that lacked endogenous expression of insulin-like growth factor II (IGF-II). These cells did not differentiate but underwent apoptotic death in low-serum differentiation medium. Death could be prevented by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling pathways involved in growth factor-mediated myoblast survival. PDGF treatment caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and -2), while IGF-I only transiently induced these enzymes. Transient transfection of a constitutively active Mek1, a specific upstream activator of ERKs, maintained myoblast viability in the absence of growth factors, while inhibition of Mek1 by the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to similar extents, only IGF-I treatment led to sustained stimulation of its downstream kinase, Akt. Transient transfection of a constitutively active PI3-kinase or an inducible Akt promoted myoblast viability in the absence of growth factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these observations demonstrate that distinct growth factor-regulated signaling pathways independently control myoblast survival. Since IGF action also stimulates muscle differentiation, these results suggest a means to regulate myogenesis through selective manipulation of different signal transduction pathways. PMID:10757809

  1. Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin

    SciTech Connect

    Charlson, Aaron T.; Zeliadt, Nicholette A.; Wattenberg, Elizabeth V.

    2009-12-01

    Palytoxin is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor because it does not bind to or activate protein kinase C. Palytoxin is thus a novel tool for investigating alternative signaling pathways that may affect carcinogenesis. We previously showed that palytoxin activates three major members of the mitogen activated protein kinase (MAPK) family, extracellular signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Here we report that palytoxin also activates another MAPK family member, called ERK5, in HeLa cells and in keratinocytes derived from initiated mouse skin (308 cells). By contrast, TPA does not activate ERK5 in these cell lines. The major cell surface receptor for palytoxin is the Na+,K+-ATPase. Accordingly, ouabain blocked the ability of palytoxin to activate ERK5. Ouabain alone did not activate ERK5. ERK5 thus represents a divergence in the signaling pathways activated by these two agents that bind to the Na+,K+-ATPase. Cycloheximide, okadaic acid, and sodium orthovanadate did not mimic the effect of palytoxin on ERK5. These results indicate that the stimulation of ERK5 by palytoxin is not simply due to inhibition of protein synthesis or inhibition of serine/threonine or tyrosine phosphatases. Therefore, the mechanism by which palytoxin activates ERK5 differs from that by which it activates ERK1/2, JNK, and p38. Finally, studies that used pharmacological inhibitors and shRNA to block ERK5 action indicate that ERK5 contributes to palytoxin-stimulated c-Fos gene expression. These results suggest that ERK5 can act as an alternative mediator for transmitting diverse tumor promoter-stimulated signals.

  2. Plant growth-promoting bacteria for phytostabilization of mine tailings.

    PubMed

    Grandlic, Christopher J; Mendez, Monica O; Chorover, Jon; Machado, Blenda; Maier, Raina M

    2008-03-15

    Eolian dispersion of mine tailings in arid and semiarid environments is an emerging global issue for which economical remediation alternatives are needed. Phytostabilization, the revegetation of these sites with native plants, is one such alternative. Revegetation often requires the addition of bulky amendments such as compost which greatly increases cost. We report the use of plant growth-promoting bacteria (PGPB) to enhance the revegetation of mine tailings and minimize the need for compost amendment. Twenty promising PGPB isolates were used as seed inoculants in a series of greenhouse studies to examine revegetation of an extremely acidic, high metal contenttailings sample previously shown to require 15% compost amendment for normal plant growth. Several isolates significantly enhanced growth of two native species, quailbush and buffalo grass, in tailings. In this study, PGPB/compost outcomes were plant specific; for quailbush, PGPB were most effective in combination with 10% compost addition while for buffalo grass, PGPB enhanced growth in the complete absence of compost. Results indicate that selected PGPB can improve plant establishment and reduce the need for compost amendment. Further, PGPB activities necessary for aiding plant growth in mine tailings likely include tolerance to acidic pH and metals. PMID:18409640

  3. Promoting growth for preterm infants following hospital discharge.

    PubMed

    Morgan, J A; Young, L; McCormick, F M; McGuire, W

    2012-07-01

    Preterm infants, especially very preterm infants, are usually growth-restricted at the time of hospital discharge. Proposed interventions to promote catch-up growth following hospital discharge include multinutrient fortification of expressed breast milk for breastfed infants and nutrient-enriched formula milk for formula-fed infants. The current evidence to support these strategies is limited. Fortification of expressed breast milk may increase weight gain and skeletal and head growth during infancy, but more research is needed to define which nutrients confer most benefit, and which population of infants is likely to receive most benefit. Trials that have assessed feeding preterm infants with commercially available nutrient-enriched formula milk ('preterm' or 'postdischarge' formulae) compared with standard formula milk have not found consistent evidence of an effect on growth parameters or development, probably because ad libitum fed infants reduce their intake relative to the calorie-density of the milk. Future studies should focus on the effect of formulae enriched with protein and minerals rather than energy and assess the effect on lean mass and skeletal growth. PMID:21406452

  4. Plant Growth-Promoting Bacteria for Phytostabilization of Mine Tailings

    SciTech Connect

    Grandlic, C.J.; Mendez, M.O.; Chorover, J.; Machado, B.; Maier, R.M.

    2009-05-19

    Eolian dispersion of mine tailings in arid and semiarid environments is an emerging global issue for which economical remediation alternatives are needed. Phytostabilization, the revegetation of these sites with native plants, is one such alternative. Revegetation often requires the addition of bulky amendments such as compost which greatly increases cost. We report the use of plant growth-promoting bacteria (PGPB) to enhance the revegetation of mine tailings and minimize the need for compost amendment. Twenty promising PGPB isolates were used as seed inoculants in a series of greenhouse studies to examine revegetation of an extremely acidic, high metal content tailings sample previously shown to require 15% compost amendment for normal plant growth. Several isolates significantly enhanced growth of two native species, quailbush and buffalo grass, in tailings. In this study, PGPB/compost outcomes were plant specific; for quailbush, PGPB were most effective in combination with 10% compost addition while for buffalo grass, PGPB enhanced growth in the complete absence of compost. Results indicate that selected PGPB can improve plant establishment and reduce the need for compost amendment. Further, PGPB activities necessary for aiding plant growth in mine tailings likely include tolerance to acidic pH and metals.

  5. Chromatographic analysis of banned antibacterial growth promoters in animal feed.

    PubMed

    Samanidou, Victoria F; Evaggelopoulou, Evaggelia N

    2008-06-01

    The issue of antimicrobial use in animals used as food is of global concern. Antimicrobials are used in animal agriculture to improve health and welfare of animals, meat quality, the economic efficiency of growth and production and public health by decreasing shedding of zoonotic pathogens. However, large quantities are often used without professional supervision. The growth-promotant (now reclassified as zootechnical feed additives) effect of low levels of antibiotics in animal feeds was first described in the late 1940s. Already in 1969 the Swann Committee recommended that use of antibiotics as a supplement in animal feedstuff should be restricted to those with little or no application as therapeutic agents for humans and animals, which would not impair the efficacy of therapeutic antibiotics through the development of resistant strains of organisms. Antimicrobials like avoparcin, ardacin, zinc bacitracin, virginiamycin, tylosin, spriramycin, carbadox and olaquindox were withdrawn within the period 1997-1999. Four others (monensin sodium, salinomycin sodium, avilamycin and flavophospholipol) were still permitted for use as growth promoters in animal feed to animals marketed in the European Union (EU). Since January 2006, they have been banned as well. This review focuses on the analytical methods developed to be an effective tool for monitoring compliance with the ban. PMID:18491356

  6. Fibroblast growth factor (FGF) signaling in development and skeletal diseases

    PubMed Central

    Teven, Chad M.; Farina, Evan M.; Rivas, Jane; Reid, Russell R.

    2014-01-01

    Fibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development. PMID:25679016

  7. HDM2 promotes WIP1-mediated medulloblastoma growth

    PubMed Central

    Buss, Meghan C.; Read, Tracy-Ann; Schniederjan, Matthew J.; Gandhi, Khanjan; Castellino, Robert C.

    2012-01-01

    Medulloblastoma is the most common malignant childhood brain tumor. The protein phosphatase and oncogene WIP1 is over-expressed or amplified in a significant number of primary human medulloblastomas and cell lines. In the present study, we examine an important mechanism by which WIP1 promotes medulloblastoma growth using in vitro and in vivo models. Human cell lines and intracerebellar xenografted animal models were used to study the role of WIP1 and the major TP53 regulator, HDM2, in medulloblastoma growth. Stable expression of WIP1 enhances growth of TP53 wild-type medulloblastoma cells, compared with cells with stable expression of an empty-vector or mutant WIP1. In an animal model, WIP1 enhances proliferation and reduces the survival of immunodeficient mice bearing intracerebellar xenografted human medulloblastoma cells. Cells with increased WIP1 expression also exhibit increased expression of HDM2. HDM2 knockdown or treatment with the HDM2 inhibitor Nutlin-3a, the active enantomer of Nutlin-3, specifically inhibits the growth of medulloblastoma cells with increased WIP1 expression. Nutlin-3a does not affect growth of medulloblastoma cells with stable expression of an empty vector or of mutant WIP1. Knockdown of WIP1 or treatment with the WIP1 inhibitor CCT007093 results in increased phosphorylation of known WIP1 targets, reduced HDM2 expression, and reduced growth specifically in WIP1 wild-type and high-expressing medulloblastoma cells. Combined WIP1 and HDM2 inhibition is more effective than WIP1 inhibition alone in blocking growth of WIP1 high-expressing medulloblastoma cells. Our preclinical study supports a role for therapies that target WIP1 and HDM2 in the treatment of medulloblastoma. PMID:22379189

  8. BMP7-induced dendritic growth in sympathetic neurons requires p75(NTR) signaling.

    PubMed

    Courter, Lauren A; Shaffo, Frances C; Ghogha, Atefeh; Parrish, Diana J; Lorentz, Christina U; Habecker, Beth A; Lein, Pamela J

    2016-09-01

    Dendritic morphology is a critical determinant of neuronal connectivity, and in postganglionic sympathetic neurons, tonic activity correlates directly with the size of the dendritic arbor. Thus, identifying signaling mechanisms that regulate dendritic arborization of sympathetic neurons is important to understanding how functional neural circuitry is established and maintained in the sympathetic nervous system. Bone morphogenetic proteins (BMPs) promote dendritic growth in sympathetic neurons; however, downstream signaling events that link BMP receptor activation to dendritic growth are poorly characterized. We previously reported that BMP7 upregulates p75(NTR) mRNA in cultured sympathetic neurons. This receptor is implicated in controlling dendritic growth in central neurons but whether p75(NTR) regulates dendritic growth in peripheral neurons is not known. Here, we demonstrate that BMP7 increases p75(NTR) protein in cultured sympathetic neurons, and this effect is blocked by pharmacologic inhibition of signaling via BMP type I receptor. BMP7 does not trigger dendritic growth in sympathetic neurons dissociated from superior cervical ganglia (SCG) of p75(NTR) nullizygous mice, and overexpression of p75(NTR) in p75(NTR) -/- neurons is sufficient to cause dendritic growth even in the absence of BMP7. Morphometric analyses of SCG from wild-type versus p75(NTR) nullizygous mice at 3, 6, and 12 to 16 weeks of age indicated that genetic deletion of p75(NTR) does not prevent dendritic growth but does stunt dendritic maturation in sympathetic neurons. These data support the hypotheses that p75(NTR) is involved in downstream signaling events that mediate BMP7-induced dendritic growth in sympathetic neurons, and suggest that p75(NTR) signaling positively modulates dendritic complexity in sympathetic neurons in vivo. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1003-1013, 2016. PMID:26663679

  9. An update on alternatives to antimicrobial growth promoters for broilers.

    PubMed

    Huyghebaert, Gerard; Ducatelle, Richard; Van Immerseel, Filip

    2011-02-01

    Livestock performance and feed efficiency are closely interrelated with the qualitative and quantitative microbial load of the animal gut, the morphological structure of the intestinal wall and the activity of the immune system. Antimicrobial growth promoters have made a tremendous contribution to profitability in intensive husbandry, but as a consequence of the increasing concern about the potential for antibiotic resistant strains of bacteria, the European Commission decided to ban all commonly used feed antibiotics. There are a number of non-therapeutic alternatives, including enzymes, (in)organic acids, probiotics, prebiotics, etheric oils and immunostimulants. Their efficacy and mode of action are briefly described in this review. PMID:20382054

  10. Redox-dependent regulation of epidermal growth factor receptor signaling.

    PubMed

    Heppner, David E; van der Vliet, Albert

    2016-08-01

    Tyrosine phosphorylation-dependent cell signaling represents a unique feature of multicellular organisms, and is important in regulation of cell differentiation and specialized cell functions. Multicellular organisms also contain a diverse family of NADPH oxidases (NOXs) that have been closely linked with tyrosine kinase-based cell signaling and regulate tyrosine phosphorylation via reversible oxidation of cysteine residues that are highly conserved within many proteins involved in this signaling pathway. An example of redox-regulated tyrosine kinase signaling involves the epidermal growth factor receptor (EGFR), a widely studied receptor system with diverse functions in normal cell biology as well as pathologies associated with oxidative stress such as cancer. The purpose of this Graphical Redox Review is to highlight recently emerged concepts with respect to NOX-dependent regulation of this important signaling pathway. PMID:26722841

  11. Redox-dependent regulation of epidermal growth factor receptor signaling

    PubMed Central

    Heppner, David E.; van der Vliet, Albert

    2015-01-01

    Tyrosine phosphorylation-dependent cell signaling represents a unique feature of multicellular organisms, and is important in regulation of cell differentiation and specialized cell functions. Multicellular organisms also contain a diverse family of NADPH oxidases (NOXs) that have been closely linked with tyrosine kinase-based cell signaling and regulate tyrosine phosphorylation via reversible oxidation of cysteine residues that are highly conserved within many proteins involved in this signaling pathway. An example of redox-regulated tyrosine kinase signaling involves the epidermal growth factor receptor (EGFR), a widely studied receptor system with diverse functions in normal cell biology as well as pathologies associated with oxidative stress such as cancer. The purpose of this Graphical Redox Review is to highlight recently emerged concepts with respect to NOX-dependent regulation of this important signaling pathway. PMID:26722841

  12. Fibroblast growth factor signaling in skeletal development and disease

    PubMed Central

    Ornitz, David M.; Marie, Pierre J.

    2015-01-01

    Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored. PMID:26220993

  13. Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development

    PubMed Central

    ten Berge, Derk; Brugmann, Samantha A.; Helms, Jill A.; Nusse, Roel

    2009-01-01

    A fundamental question in developmental biology is how does an undifferentiated field of cells acquire spatial pattern and undergo coordinated differentiation? The development of the vertebrate limb is an important paradigm for understanding these processes. The skeletal and connective tissues of the developing limb all derive from a population of multipotent progenitor cells located in its distal tip. During limb outgrowth, these progenitors segregate into a chondrogenic lineage, located in the center of the limb bud, and soft connective tissue lineages located in its periphery. We report that the interplay of two families of signaling proteins, fibroblast growth factors (FGFs) and Wnts, coordinate the growth of the multipotent progenitor cells with their simultaneous segregation into these lineages. FGF and Wnt signals act together to synergistically promote proliferation while maintaining the cells in an undifferentiated, multipotent state, but act separately to determine cell lineage specification. Withdrawal of both signals results in cell cycle withdrawal and chondrogenic differentiation. Continued exposure to Wnt, however, maintains proliferation and re-specifies the cells towards the soft connective tissue lineages. We have identified target genes that are synergistically regulated by Wnts and FGFs, and show how these factors actively suppress differentiation and promote growth. Finally, we show how the spatial restriction of Wnt and FGF signals to the limb ectoderm, and to a specialized region of it, the apical ectodermal ridge, controls the distribution of cell behaviors within the growing limb, and guides the proper spatial organization of the differentiating tissues. PMID:18776145

  14. Growth inhibitors and promoters examplified on solution growth of paraffin crystals

    NASA Astrophysics Data System (ADS)

    Kern, R.; Dassonville, R.

    1992-01-01

    Additives, called also intentional impurities, act on crystal growth kinetics. Generally, they are very specific and some act as inhibitors, others as promoters. Paraffin solution growth is sensitive to organic additive molecules and especially to polymers. In the latter case, the same molecule is able to act both as an inhibitor and as a promoter, depending only on its degree of polymerisation m. Polyalkylacrylate with low m value slows down the precipitation kinetics of n-paraffins, with species forming mestable solid solutions. On the contrary, high m values promote the precipitation, provided the polymer crystallizes prior to paraffin precipitation. In this case the polymer crystals act as epitaxial seeds, leading to paraffin crystal agglomerates of large size. This versatility of some polymers is of great help in industrial processes where paraffin crystals are involved.

  15. MiR-328 promotes glioma cell invasion via SFRP1-dependent Wnt-signaling activation.

    PubMed

    Delic, Sabit; Lottmann, Nadine; Stelzl, Anja; Liesenberg, Franziska; Wolter, Marietta; Götze, Silke; Zapatka, Marc; Shiio, Yuzuru; Sabel, Michael C; Felsberg, Jörg; Reifenberger, Guido; Riemenschneider, Markus J

    2014-01-01

    Background Diffusely infiltrative growth of human astrocytic gliomas is one of the major obstacles to successful tumor therapy. Thorough insights into the molecules and pathways signaling glioma cell invasion thus appear of major relevance for the development of targeted and individualized therapies. By miRNA expression profiling of microdissected human tumor biopsy specimens we identified miR-328 as one of the main miRNAs upregulated in invading glioma cells in vivo and further investigated its role in glioma pathogenesis. Methods We employed miRNA mimics and inhibitors to functionally characterize miR-328, 3' untranslated region luciferase assays, and T-cell factor/lymphoid enhancer factor reporter assays to pinpoint miR-328 targets and signaling pathways, and analyzed miR-328 expression in a large panel of gliomas. Results First, we corroborated the invasion-promoting role of miR-328 in A172 and TP365MG glioma cells. Secreted Frizzled-related protein 1 (SFRP1), an inhibitor of Wnt signaling, was then pinpointed as a direct miR-328 target. SFRP1 expression is of prognostic relevance in gliomas with reduced expression, being associated with significantly lower overall patient survival in both the Repository of Molecular Brain Neoplasia Data (REMBRANDT) and The Cancer Genome Atlas. Of note, miR-328 regulated both SFRP1 protein expression levels and Wnt signaling pathway activity. Finally, in human glioma tissues miR-328 appeared to account for the downregulation of SFRP1 preferentially in lower-grade astrocytic gliomas and was inversely related to SFRP1 promoter hypermethylation. Conclusion Taken together, we report on a novel molecular miR-328-dependent mechanism that via SFRP1 inhibition and Wnt activation contributes to the infiltrative glioma phenotype at already early stages of glioma progression, with unfavorable prognostic implications for the final outcome of the disease. PMID:24305703

  16. Plant Growth-Promoting Rhizobacteria Stimulate Vegetative Growth and Asexual Reproduction of Kalanchoe daigremontiana.

    PubMed

    Park, Yong-Soon; Park, Kyungseok; Kloepper, Joseph W; Ryu, Choong-Min

    2015-09-01

    Certain bacterial species associate with plant roots in soil. The plant growth-promoting rhizobacteria (PGPR) stimulate plant growth and yield in greenhouse and field. Here, we examined whether application of known bacilli PGPR strains stimulated growth and asexual reproduction in the succulent plant Kalanchoe daigremontiana. Four PGPR strains B. amyloliquefaciens IN937a, B. cereus BS107, B. pumilus INR7, and B. subtilis GB03 were applied to young plantlets by soil-drenching, and plant growth and development was monitored for three months. Aerial growth was significantly stimulated in PGPR-inoculated plants, which was observed as increases in plant height, shoot weight, and stem width. The stimulated growth influenced plant development by increasing the total number of leaves per plant. Treatment with bacilli also increased the total root biomass compared with that of control plants, and led to a 2-fold increase in asexual reproduction and plantlet formation on the leaf. Collectively, our results firstly demonstrate that Bacillus spp. promote vegetative development of K. daigremontiana, and the enhanced growth stimulates asexual reproduction and plantlet formation. PMID:26361480

  17. Plant Growth-Promoting Rhizobacteria Stimulate Vegetative Growth and Asexual Reproduction of Kalanchoe daigremontiana

    PubMed Central

    Park, Yong-Soon; Park, Kyungseok; Kloepper, Joseph W.; Ryu, Choong-Min

    2015-01-01

    Certain bacterial species associate with plant roots in soil. The plant growth-promoting rhizobacteria (PGPR) stimulate plant growth and yield in greenhouse and field. Here, we examined whether application of known bacilli PGPR strains stimulated growth and asexual reproduction in the succulent plant Kalanchoe daigremontiana. Four PGPR strains B. amyloliquefaciens IN937a, B. cereus BS107, B. pumilus INR7, and B. subtilis GB03 were applied to young plantlets by soil-drenching, and plant growth and development was monitored for three months. Aerial growth was significantly stimulated in PGPR-inoculated plants, which was observed as increases in plant height, shoot weight, and stem width. The stimulated growth influenced plant development by increasing the total number of leaves per plant. Treatment with bacilli also increased the total root biomass compared with that of control plants, and led to a 2-fold increase in asexual reproduction and plantlet formation on the leaf. Collectively, our results firstly demonstrate that Bacillus spp. promote vegetative development of K. daigremontiana, and the enhanced growth stimulates asexual reproduction and plantlet formation. PMID:26361480

  18. Tumor-promoting functions of transforming growth factor-β in progression of cancer

    PubMed Central

    2012-01-01

    Transforming growth factor-β (TGF-β) elicits both tumor-suppressive and tumor-promoting functions during cancer progression. Here, we describe the tumor-promoting functions of TGF-β and how these functions play a role in cancer progression. Normal epithelial cells undergo epithelial-mesenchymal transition (EMT) through the action of TGF-β, while treatment with TGF-β and fibroblast growth factor (FGF)-2 results in transdifferentiation into activated fibroblastic cells that are highly migratory, thereby facilitating cancer invasion and metastasis. TGF-β also induces EMT in tumor cells, which can be regulated by oncogenic and anti-oncogenic signals. In addition to EMT promotion, invasion and metastasis of cancer are facilitated by TGF-β through other mechanisms, such as regulation of cell survival, angiogenesis, and vascular integrity, and interaction with the tumor microenvironment. TGF-β also plays a critical role in regulating the cancer-initiating properties of certain types of cells, including glioma-initiating cells. These findings thus may be useful for establishing treatment strategies for advanced cancer by inhibiting TGF-β signaling. PMID:22111550

  19. Combinatorial Fibronectin and Laminin Signaling Promote Highly Efficient Cardiac Differentiation of Human Embryonic Stem Cells

    PubMed Central

    Sa, Silin; Wong, Lian

    2014-01-01

    Abstract Cardiomyocytes (CMs) differentiated from human embryonic stem cells (hESCs) are a promising and potentially unlimited cell source for myocardial repair and regeneration. Recently, multiple methodologies—primarily based on the optimization of growth factors—have been described for efficient cardiac differentiation of hESCs. However, the role of extracellular matrix (ECM) signaling in CM differentiation has not yet been explored fully. This study examined the role of ECM signaling in the efficient generation of CMs from both H7 and H9 ESCs. The hESCs were differentiated on ECM substrates composed of a range of fibronectin (FN) and laminin (LN) ratios and gelatin and evaluated by the fluorescence activated cell scanning (FACS) analysis on day 14. Of the ECM substrates examined, the 70:30 FN:LN reproducibly generated the greatest numbers of CMs from both hESC lines. Moreover, the LN receptor integrin β4 (ITGB4) and FN receptor integrin β5 (ITGB5) genes, jointly with increased phosphorylated focal adhension kinase and phosphorylated extracellular signal-regulated kinases (p-ERKs), were up-regulated over 13-fold in H7 and H9 cultured on 70:30 FN:LN compared with gelatin. Blocking studies confirmed the role of all these molecules in CM specification, suggesting that the 70:30 FN:LN ECM promotes highly efficient differentiation of CMs through the integrin-mediated MEK/ERK signaling pathway. Lastly, the data suggest that FN:LN-induced signaling utilizes direct cell-to-cell signaling from distinct ITGB4+ and ITGB5+ cells. PMID:25126479

  20. PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling

    SciTech Connect

    Yamada, Tamaki; Tsuda, Masumi; Ohba, Yusuke Kawaguchi, Hideaki; Totsuka, Yasunori; Shindoh, Masanobu

    2008-04-11

    Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer.

  1. Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node.

    PubMed

    Seoane, S; Montero, J C; Ocaña, A; Pandiella, A

    2016-05-01

    Advances in the treatment of breast cancer have resulted in increased survival. However, in the metastatic setting, the disease remains incurable. Therefore, understanding of the mechanisms that promote dissemination of breast cancer cells may favor the development of novel therapeutic strategies to fight those tumors. Here, we show that the ErbB ligands, Neuregulins (NRGs), promote metastatic dissemination of breast cancer cells by switching on a kinase-metalloproteinase network. Clinicopathological analyses demonstrated that NRG expression in breast tumors associated to lymph node invasion and poor patient outcome. Preclinical in vivo analyses showed that NRG expression favored in situ tumor growth, local spreading and metastatic dissemination. Genomic, biochemical and functional studies identified matrix metalloproteinases, particularly stromelysin 2 and collagenase 3, as key mediators of the NRG-induced dissemination properties of breast cancer cells. Mechanistic analyses demonstrated that NRG augmented metalloproteinase expression through a route controlled by ERK1/2 kinases. ERK1/2 increased collagenase 3 expression by controlling the activity of an SBF1-related transcription factor. In conclusion, we describe a pathway linked to breast cancer dissemination. The clinical availability of agents that target some of the components of this signalling pathway suggests that patients with tumors fed by NRGs or other factors able to activate the ERK-Collagenase 3 route may benefit from agents that act on that signalling axis. PMID:26364598

  2. Beclin 1 regulates growth factor receptor signaling in breast cancer.

    PubMed

    Rohatgi, R A; Janusis, J; Leonard, D; Bellvé, K D; Fogarty, K E; Baehrecke, E H; Corvera, S; Shaw, L M

    2015-10-16

    Beclin 1 is a haploinsufficient tumor suppressor that is decreased in many human tumors. The function of beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy. However, beclin 1 is a core component of the vacuolar protein sorting 34 (Vps34)/class III phosphatidylinositoI-3 kinase (PI3KC3) and Vps15/p150 complex that regulates multiple membrane-trafficking events. In the current study, we describe an alternative mechanism of action for beclin 1 in breast cancer involving its control of growth factor receptor signaling. We identify a specific stage of early endosome maturation that is regulated by beclin 1, the transition of APPL1-containing phosphatidyIinositol 3-phosphate-negative (PI3P(-)) endosomes to PI3P(+) endosomes. Beclin 1 regulates PI3P production in response to growth factor stimulation to control the residency time of growth factor receptors in the PI3P(-)/APPL(+)-signaling-competent compartment. As a result, suppression of BECN1 sustains growth factor-stimulated AKT and ERK activation resulting in increased breast carcinoma cell invasion. In human breast tumors, beclin 1 expression is inversely correlated with AKT and ERK phosphorylation. Our data identify a novel role for beclin 1 in regulating growth factor signaling and reveal a mechanism by which loss of beclin 1 expression would enhance breast cancer progression. PMID:25639875

  3. A biosensor for organoarsenical herbicides and growth promoters

    PubMed Central

    Chen, Jian; Sun, Samio; Li, Chen-Zhong; Zhu, Yong-Guan; Rosen, Barry P.

    2014-01-01

    The toxic metalloid arsenic is widely distributed in food, water, and soil. While inorganic arsenic enters the environment primarily from geochemical sources, methylarsenicals either result from microbial biotransformation of inorganic arsenic or are introduced anthropogenically. Methylarsenicals such as monosodium methylarsonic acid (MSMA) have been extensively utilized as herbicides, and aromatic arsenicals such as roxarsone (Rox) are used as growth promoters for poultry and swine. Organoarsenicals are degraded to inorganic arsenic. The toxicological effects of arsenicals depend on their oxidation state, chemical composition, and bioavailability. Here we report that the active forms are the trivalent arsenic-containing species. We constructed a whole-cell biosensor utilizing a modified ArsR repressor that is highly selective toward trivalent methyl and aromatic arsenicals, with essentially no response to inorganic arsenic. The biosensor was adapted for in vitro detection of organoarsenicals using fluorescence anisotropy of ArsR-DNA interactions. It detects bacterial biomethylation of inorganic arsenite both in vivo and in vitro with detection limits of 10−7 M and linearity to 10−6 M for phenylarsenite and 5×10−6 M for methylarsenite. The biosensor detects reduced forms of MSMA and roxarsone and offers a practical, low cost method for detecting activate forms and breakdown products of organoarsenical herbicides and growth promoters. PMID:24359149

  4. Growth promotion effect of steelmaking slag on Spirulina platensis

    NASA Astrophysics Data System (ADS)

    Nogami, R.; Tam, L. T.; Anh, H. T. L.; Quynh, H. T. H.; Thom, L. T.; Nhat, P. V.; Thu, N. T. H.; Hong, D. D.; Wakisaka, M.

    2016-04-01

    A growth promotion effect of steelmaking slag on Spirulina platensis M135 was investigated. The growth promotion effect was obtained that was 1.27 times greater than that obtained by the control by adding 500 mg L‑1 of steelmaking slag and culturing for 60 days. The lipid content decreased in a concentration-dependent manner with steelmaking slag, whereas the carbohydrate content remained constant. The protein content of S. platensis M135 increased in a concentration-dependent manner with steelmaking slag when cultured at day 45. The superoxide dismutase activity of S. platensis M135 exhibited a decreasing trend in a time-dependent manner and an increasing trend in the control. The superoxide dismutase activity was lower than that of the control at day 1 but was higher at day 30. No genetic damage was observed up to 500 mg L‑1 of steelmaking slag at 30 days of culture. Recovery from genetic damage was observed at 1,000 mg L‑1 of steelmaking slag but not at higher concentrations.

  5. Metastasis-associated lung adenocarcinoma transcript 1 promotes the proliferation of chondrosarcoma cell via activating Notch-1 signaling pathway

    PubMed Central

    Xu, Fengqin; Zhang, Zhi-qiang; Fang, Yong-chao; Li, Xiao-lei; Sun, Yu; Xiong, Chuan-zhi; Yan, Lian-qi; Wang, Qiang

    2016-01-01

    Background Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) is identified to be overexpressed in several cancers. However, the role of MALAT-1 in chondrosarcoma is poorly understood. Methods The expression of MALAT-1 and Notch-1 signaling pathway was detected in chondrosarcoma tissues and chondrosarcoma cells by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to examine the cell viability of chondrosarcoma cells transfected with si-MALAT-1 or pcDNA-MALAT-1. Then the expression of Notch-1 signaling pathway was detected when MALAT-1 was upregulated or downregulated in chondrosarcoma cells. A subcutaneous chondrosarcoma cells xenograft model was used to confirm the effect of MALAT-1 on tumor growth in vivo. Results We found the increased expression of MALAT-1 and Notch-1 signaling pathway in chondrosarcoma tissue and cells. MALAT-1 promoted the proliferation of chondrosarcoma cells. In addition, MALAT-1 activated the Notch-1 signaling pathway at posttranscriptional level in chondrosarcoma cells. Meanwhile, overexpression of Notch-1 reversed the effect of si-MALAT-1 on the proliferation of chondrosarcoma cells. Finally, we found that MALAT-1 promoted the tumor growth in a subcutaneous chondrosarcoma cells xenograft model, which confirmed the promoted effect of MALAT-1 on the tumor growth in vivo. Conclusion Taken together, our study demonstrated that MALAT-1 promoted the proliferation of chondrosarcoma cell via activating Notch-1 signaling pathway. PMID:27110130

  6. Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?

    PubMed Central

    Laukkanen, Mikko O.

    2016-01-01

    Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2−) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction. PMID:27293512

  7. Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?

    PubMed

    Laukkanen, Mikko O

    2016-01-01

    Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2 (-)) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction. PMID:27293512

  8. EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells.

    PubMed

    Castanieto, Angela; Johnston, Michael J; Nystul, Todd G

    2014-01-01

    Epithelial stem cells divide asymmetrically, such that one daughter replenishes the stem cell pool and the other differentiates. We found that, in the epithelial follicle stem cell (FSC) lineage of the Drosophila ovary, epidermal growth factor receptor (EGFR) signaling functions specifically in the FSCs to promote the unique partially polarized state of the FSC, establish apical-basal polarity throughout the lineage, and promote FSC maintenance in the niche. In addition, we identified a novel connection between EGFR signaling and the cell-polarity regulator liver kinase B1 (LKB1), which indicates that EGFR signals through both the Ras-Raf-MEK-Erk pathway and through the LKB1-AMPK pathway to suppress apical identity. The development of apical-basal polarity is the earliest visible difference between FSCs and their daughters, and our findings demonstrate that the EGFR-mediated regulation of apical-basal polarity is essential for the segregation of stem cell and daughter cell fates. PMID:25437306

  9. Isolation and characterization of plant growth-promoting rhizobacteria from wheat rhizosphere and their effect on plant growth promotion.

    PubMed

    Majeed, Afshan; Abbasi, M Kaleem; Hameed, Sohail; Imran, Asma; Rahim, Nasir

    2015-01-01

    The present study was conducted to characterize the native plant growth promoting (PGP) bacteria from wheat rhizosphere and root-endosphere in the Himalayan region of Rawalakot, Azad Jammu and Kashmir (AJK), Pakistan. Nine bacterial isolates were purified, screened in vitro for PGP characteristics and evaluated for their beneficial effects on the early growth of wheat (Triticum aestivum L.). Among nine bacterial isolates, seven were able to produce indole-3- acetic acid in tryptophan-supplemented medium; seven were nitrogen fixer, and four were able to solubilize inorganic phosphate in vitro. Four different morphotypes were genotypically identified based on IGS-RFLP fingerprinting and representative of each morphotype was identified by 16S rRNA gene sequencing analysis except Gram-positive putative Bacillus sp. Based on 16S rRNA gene sequence analysis, bacterial isolates AJK-3 and AJK-9 showing multiple PGP-traits were identified as Stenotrophomonas spp. while AJK-7 showed equal homologies to Acetobacter pasteurianus and Stenotrophomonas specie. Plant inoculation studies indicated that these Plant growth-promoting rhizobacteria (PGPR) strains provided a significant increase in shoot and root length, and shoot and root biomass. A significant increase in shoot N contents (up to 76%) and root N contents (up to 32%) was observed over the un-inoculated control. The study indicates the potential of these PGPR for inoculums production or biofertilizers for enhancing growth and nutrient content of wheat and other crops under field conditions. The study is the first report of wheat associated bacterial diversity in the Himalayan region of Rawalakot, AJK. PMID:25852661

  10. Isolation and characterization of plant growth-promoting rhizobacteria from wheat rhizosphere and their effect on plant growth promotion

    PubMed Central

    Majeed, Afshan; Hameed, Sohail; Imran, Asma; Rahim, Nasir

    2015-01-01

    The present study was conducted to characterize the native plant growth promoting (PGP) bacteria from wheat rhizosphere and root-endosphere in the Himalayan region of Rawalakot, Azad Jammu and Kashmir (AJK), Pakistan. Nine bacterial isolates were purified, screened in vitro for PGP characteristics and evaluated for their beneficial effects on the early growth of wheat (Triticum aestivum L.). Among nine bacterial isolates, seven were able to produce indole-3- acetic acid in tryptophan-supplemented medium; seven were nitrogen fixer, and four were able to solubilize inorganic phosphate in vitro. Four different morphotypes were genotypically identified based on IGS-RFLP fingerprinting and representative of each morphotype was identified by 16S rRNA gene sequencing analysis except Gram-positive putative Bacillus sp. Based on 16S rRNA gene sequence analysis, bacterial isolates AJK-3 and AJK-9 showing multiple PGP-traits were identified as Stenotrophomonas spp. while AJK-7 showed equal homologies to Acetobacter pasteurianus and Stenotrophomonas specie. Plant inoculation studies indicated that these Plant growth-promoting rhizobacteria (PGPR) strains provided a significant increase in shoot and root length, and shoot and root biomass. A significant increase in shoot N contents (up to 76%) and root N contents (up to 32%) was observed over the un-inoculated control. The study indicates the potential of these PGPR for inoculums production or biofertilizers for enhancing growth and nutrient content of wheat and other crops under field conditions. The study is the first report of wheat associated bacterial diversity in the Himalayan region of Rawalakot, AJK. PMID:25852661

  11. Differential growth responses of Brachypodium distachyon genotypes to inoculation with plant growth promoting rhizobacteria.

    PubMed

    do Amaral, Fernanda P; Pankievicz, Vânia C S; Arisi, Ana Carolina M; de Souza, Emanuel M; Pedrosa, Fabio; Stacey, Gary

    2016-04-01

    Plant growth promoting rhizobacteria (PGPR) can associate and enhance the growth of important crop grasses. However, in most cases, the molecular mechanisms responsible for growth promotion are not known. Such research could benefit by the adoption of a grass model species that showed a positive response to bacterial inoculation and was amenable to genetic and molecular research methods. In this work we inoculated different genotypes of the model grass Brachypodium distachyon with two, well-characterized PGPR bacteria, Azospirillum brasilense and Herbaspirillum seropedicae, and evaluated the growth response. Plants were grown in soil under no nitrogen or with low nitrogen (i.e., 0.5 mM KNO3). A variety of growth parameters (e.g., shoot height, root length, number of lateral roots, fresh and dry weight) were measured 35 days after inoculation. The data indicate that plant genotype plays a very important role in determining the plant response to PGPR inoculation. A positive growth response was observed with only four genotypes grown under no nitrogen and three genotypes tested under low nitrogen. However, in contrast, relatively good root colonization was seen with most genotypes, as measured by drop plate counting and direct, microscopic examination of roots. In particular, the endophytic bacteria H. seropedicae showed strong epiphytic and endophytic colonization of roots. PMID:26873699

  12. Sensing Vegetation Growth and Senescence with Reflected GPS Signals

    NASA Astrophysics Data System (ADS)

    Evans, S. G.; Small, E. E.; Larson, K. M.; Rocco, M.

    2012-12-01

    We have developed a new technique to estimate vegetation growth and senescence using reflected GPS signals (multipath) measured by geodetic-quality GPS stations. The sensing footprint is ~1000 m2, larger than that provided by typical in situ observations but smaller than that from space-based products. Because GPS satellites transmit L-band signals, the vegetation estimates derived from GPS reflections are a measure of vegetation water content, not greenness as is the case for optical remote sensing methods. We present results based on two distinct attributes of the multipath signal: (1) signal attenuation observed as the amplitude of the signal-to-noise (SNR) interference pattern; and (2) diffuse scattering measured via an operational GPS noise statistic, MP1rms. We have compared GPS multipath to biweekly measurements of biomass, vegetation height, and water content at ten test sites that span a range of vegetation characteristics. Vegetation height and water content are inversely correlated with amplitude of the SNR signal. The reflected signal is completely suppressed when vegetation water content exceeds 3 kg m-2, for example at peak growth at irrigated corn and alfalfa sites. We have also examined GPS data from hundreds of sites in NSF's Plate Boundary Observatory (PBO) network to more completely evaluate this method. These sites are located in the western U.S. where grasses and shrubs are dominant. The operational MP1rms statistic, a measure of multipath scattering, exhibits a clear seasonal cycle as expected for vegetation growth and senescence. MP1rms is inversely correlated with Normalized Difference Vegetative Index (NDVI) at most PBO sites: there is more scattering of L-band signals at times when vegetation is greener. The MP1rms variations lag NDVI by approximately three weeks, consistent with the idea that green-up precedes plant growth. We measured biomass, vegetation water content, and height at 25 PBO sites in Western California. Field sampling was

  13. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling.

    PubMed

    Bush, Erik W; Hood, David B; Papst, Philip J; Chapo, Joseph A; Minobe, Wayne; Bristow, Michael R; Olson, Eric N; McKinsey, Timothy A

    2006-11-01

    The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear. Here, we demonstrate that diverse signals for cardiac hypertrophy stimulate expression of canonical transient receptor potential (TRPC) channels. TRPC consists of a family of seven membrane-spanning nonselective cation channels that have been implicated in the nonvoltage-gated influx of calcium in response to G protein-coupled receptor signaling, receptor tyrosine kinase signaling, and depletion of internal calcium stores. TRPC3 expression is up-regulated in multiple rodent models of pathological cardiac hypertrophy, whereas TRPC5 expression is induced in failing human heart. We demonstrate that TRPC promotes cardiomyocyte hypertrophy through activation of calcineurin and its downstream effector, the nuclear factor of activated T cells transcription factor. These results define a novel role for TRPC channels in the control of cardiac growth, and suggest that a TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart. PMID:16950785

  14. Atrazine promotes RM1 prostate cancer cell proliferation by activating STAT3 signaling.

    PubMed

    Hu, Kebang; Tian, Yong; Du, Yanwei; Huang, Liandi; Chen, Junyu; Li, Na; Liu, Wei; Liang, Zuowen; Zhao, Lijing

    2016-05-01

    Atrazine, a widely used pesticide, is frequently detected in soil and surface water, which alarms epidemiologists and medical professionals because of its potential deleterious effects on health. Indeed, atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. Both animal and human studies have suggested that atrazine is possibly carcinogenic, although discrepant results have been reported. In this study, RM1 cells were used to explore the atrazine effects on prostate cancer. Proliferation, migration and invasion of RM1 cells were assessed by colony formation, wound-healing and invasion assays, respectively, after in vitro exposure to atrazine. In addition, an RM1 cell xenograft model was generated to evaluate the effects of atrazine in vivo. To explore the molecular mechanisms, qRT‑PCR, immunohistochemistry, and western blot analyses were employed to detect mRNA and protein levels of STAT3 signaling and cell cycle related proteins, including p53, p21, cyclin B1 and cyclin D1. Interestingly, RM1 cell proliferation was increased after treatment with atrazine, concomitantly with STAT3 signaling activation. These results suggest that atrazine promotes RM1 cell growth in vitro and in vivo by activating STAT3 signaling. PMID:26984284

  15. Key roles of necroptotic factors in promoting tumor growth.

    PubMed

    Liu, Xinjian; Zhou, Min; Mei, Ling; Ruan, Jiaying; Hu, Qian; Peng, Jing; Su, Hang; Liao, Hong; Liu, Shanling; Liu, WeiPing; Wang, He; Huang, Qian; Li, Fang; Li, Chuan-Yuan

    2016-04-19

    Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage-independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-κB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro-necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment. PMID:26959742

  16. Key roles of necroptotic factors in promoting tumor growth

    PubMed Central

    Liu, Xinjian; Zhou, Min; Mei, Ling; Ruan, Jiaying; Hu, Qian; Peng, Jing; Su, Hang; Liao, Hong; Liu, Shanling; Liu, WeiPing; Wang, He; Huang, Qian; Li, Fang; Li, Chuan-Yuan

    2016-01-01

    Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage-independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-κB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro-necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment. PMID:26959742

  17. Increased local dopamine secretion has growth promoting effects in cholangiocarcinoma

    PubMed Central

    Coufal, Monique; Invernizzi, Pietro; Gaudio, Eugenio; Bernuzzi, Francesca; Frampton, Gabriel A.; Onori, Paolo; Franchitto, Antonio; Carpino, Guido; Ramirez, Jonathan C.; Alvaro, Domenico; Marzioni, Marco; Battisti, Guido; Benedetti, Antonio; DeMorrow, Sharon

    2009-01-01

    Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We have previously shown that serotonin metabolism is dysregulated in cholangiocarcinoma leading to an increased secretion of serotonin, which has growth-promoting effects. Because serotonin and dopamine share the degradation machinery, we evaluated the secretion of dopamine from cholangiocarcinoma and its effects on cell proliferation. Using 4 cholangiocarcinoma cell lines and human biopsy samples, we demonstrated that there was an increase in mRNA and protein expression of the dopamine synthesis enzymes tyrosine hydroxylase and dopa decarboxylase in cholangiocarcinoma. There was increased dopamine secretion from cholangiocarcinoma cell lines compared to H69 and HIBEC cholangiocytes and increased dopamine immunoreactivity in human biopsy samples. Furthermore, administration of dopamine to all cholangiocarcinoma cell lines studied increased proliferation by up to 30% which could be blocked by the pretreatment of the D2 and D4 dopamine receptor antagonists, whereas blocking dopamine production by α-methyldopa administration suppressed growth by up to 25%. Administration of α-methyldopa to nude mice also suppressed cholangiocarcinoma tumor growth. The data presented here represent the first evidence that dopamine metabolism is dysregulated in cholangiocarcinoma and that modulation of dopamine synthesis may represent an alternative target for the development of therapeutic strategies. PMID:19795457

  18. Cost-effectiveness of growth monitoring and promotion.

    PubMed

    Dixon, R A

    1993-08-01

    50 million children/year are in growth monitoring and promotion (GMP) programs in developing countries and 30 million growth charts are printed annually in India alone. GMP is a simple technology of weighing and charting, but it must be properly implemented under conditions that are conducive to program success. Critics of GMP argue that its effectiveness remains to be proved. If GMP programs lead to improved growth, health, and nutritional status, will it work when expanded to the national level and is it cost-effective? A community intervention trial in South India considered the cost-effectiveness component of these concerns, but yielded only mixed results and the recommendation that replicate studies be conducted in other countries. An observational study of 179 health workers in 100 rural health facilities in 9 developing countries found deficiencies so severe in weighing, plotting, and interpreting that GMP activities simply consumed time and resources which could have been better allocated elsewhere within the health system. GMP is unlikely to succeed in the absence of training and supervision for assessment, analysis, and action. Community involvement in and ownership of GMP are also recommended. PMID:8101577

  19. IGF-1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors

    PubMed Central

    Rota, Lauren M.; Albanito, Lidia; Shin, Marcus E.; Goyeneche, Corey L.; Shushanov, Sain; Gallagher, Emily J.; LeRoith, Derek; Lazzarino, Deborah A.; Wood, Teresa L.

    2014-01-01

    Triple-negative breast cancers (TNBC) are an aggressive disease subtype which unlike other subtypes lack an effective targeted therapy. Inhibitors of the insullin-like growth factor receptor (IGF-1R) have been considered for use in treating TNBC. Here we provide genetic evidence that IGF-1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt-1 and mutant IGF-1R, a reduction in IGF-1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamal cell phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29hi/CD24+) and luminal (CD24+/CD61+/CD29lo) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacological inhibition of the IGF-1R in vitro was sufficient to increase the tumorsphere-forming efficiency of MMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor vs the IR-B isoform, which in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors an attenuation of IGF-1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes, with potential implications for understanding TNBC pathobiology and treatment. PMID:25092896

  20. Over-expression of prothymosin-α antagonizes TGFβ signalling to promote the development of emphysema.

    PubMed

    Su, Bing-Hua; Tseng, Yau-Lin; Shieh, Gia-Shing; Chen, Yi-Cheng; Wu, Pensee; Shiau, Ai-Li; Wu, Chao-Liang

    2016-02-01

    Emphysema, a major consequence of chronic obstructive pulmonary disease (COPD), is characterized by the permanent airflow restriction resulting from enlargement of alveolar airspace and loss of lung elasticity. Transforming growth factor-β (TGFβ) signalling regulates the balance of matrix metalloproteinase (MMP)/tissue inhibitor of matrix metalloproteinase (TIMP) to control matrix homeostasis. Patients with COPD have dysregulated TGFβ signalling and reduced histone deacetylase (HDAC) activity through epigenetic up-regulation of histone acetylation in the promoters of pro-inflammatory genes. However, the potential link between decreased HDAC activity and dysregulated TGFβ signalling in emphysema pathogenesis remains to be determined. Prothymosin α (ProT), a highly conserved acidic nuclear protein, plays a role in the acetylation of histone and non-histone proteins. The aim of this study was to test the hypothesis that ProT inhibits TGFβ-Smad signalling through Smad7, thereby contributing to emphysema pathogenesis. We show that ProT enhances Smad7 acetylation by decreasing its association with HDAC and thereby down-regulates TGFβ-Smad signalling. ProT caused an imbalance between MMP and TIMP through acetylated Smad7 in favour of MMP expression. In addition to interfering with R-Smad activation and targeting receptors for degradation in the cytoplasm, acetylated Smad7 potentiated by ProT competitively antagonized binding of the pSmad2/3-Smad4 complex to the TIMP-3 promoter, resulting in reduced TIMP-3 expression. These effects were detected in ProT-over-expressing cells, lungs of ProT transgenic mice displaying an emphysema phenotype and in emphysema patients. Importantly, increased Smad7 and reduced TIMP-3 were found in the lungs of emphysema patients and mice with cigarette smoke extract (CSE)-induced emphysema. Such effects could be abrogated by silencing endogenous ProT expression. Collectively, our results uncover acetylated Smad7 regulated by ProT as an

  1. Norcantharidin blocks Wnt/β-catenin signaling via promoter demethylation of WIF-1 in glioma.

    PubMed

    Xie, Dajiang; Xie, Jixi; Wan, Yingfeng; Ma, Li; Qi, Xuchen; Wang, Kun; Yang, Shuxu

    2016-04-01

    Glioma is one of the most common primary intracranial tumors, and the prognosis is poor even though much treatment management is employed. Wnt/β-catenin signaling has been reported to be associated with glioma. Norcantharidin (NCTD) is the demethylated analog of cantharidin isolated from blister beetles, and it is reported to possess anticancer activity but less nephrotoxicity than cantharidin. Accordingly, we aimed to investigate NCTD as an anti-neoplastic drug that inhibits the Wnt/β‑catenin pathway via promoter demethylation of Wnt inhibitory factor-1 (WIF-1) in glioma growth in vitro. In the present study, we report that NCTD inhibited cell proliferation, induced apoptosis and cell cycle arrest, and suppressed cell migration and invasion in vitro. Moreover, we observed that the expression levels of WIF-1 mRNA and protein in the NCTD-treated cells were increased significantly compared with these levels in the negative control (NC) cells. Promoter demethylation was observed in the NCTD‑treated cells. In contrast, aberrant methylation was observed in the NC cells. Additionally, more investigation revealed that NCTD suppressed activity of Wnt/β-catenin signaling and transcription of β-catenin/TCF-4. Furthermore, the expression of apoptosis-related proteins Bcl-2 and cleaved caspase-3 indicated significant cell apoptosis. We provide initial evidence that NCTD reactivates WIF-1 from a methylation state, and downregulates canonical Wnt/β-catenin signaling. Our findings revealed that NCTD is effective for glioma in vitro and may be a new therapeutic option in vivo. PMID:26781164

  2. Notch signaling promotes osteoclast maturation and resorptive activity.

    PubMed

    Ashley, Jason W; Ahn, Jaimo; Hankenson, Kurt D

    2015-11-01

    The role of Notch signaling in osteoclast differentiation is controversial with conflicting experimental evidence indicating both stimulatory and inhibitory roles. Differences in experimental protocols and in vivo versus in vitro models may explain the discrepancies between studies. In this study, we investigated cell autonomous roles of Notch signaling in osteoclast differentiation and function by altering Notch signaling during osteoclast differentiation using stimulation with immobilized ligands Jagged1 or Delta-like1 or by suppression with γ-secretase inhibitor DAPT or transcriptional inhibitor SAHM1. Stimulation of Notch signaling in committed osteoclast precursors resulted in larger osteoclasts with a greater number of nuclei and resorptive activity whereas suppression resulted in smaller osteoclasts with fewer nuclei and suppressed resorptive activity. Conversely, stimulation of Notch signaling in osteoclast precursors prior to induction of osteoclastogenesis resulted in fewer osteoclasts. Our data support a mechanism of context-specific Notch signaling effects wherein Notch stimulation inhibits commitment to osteoclast differentiation, but enhances the maturation and function of committed precursors. PMID:25914241

  3. p38 MAPK Signaling in Postnatal Tendon Growth and Remodeling

    PubMed Central

    Schwartz, Andrew J.; Sarver, Dylan C.; Sugg, Kristoffer B.; Dzierzawski, Justin T.; Gumucio, Jonathan P.; Mendias, Christopher L.

    2015-01-01

    Tendon is a dynamic tissue whose structure and function is influenced by mechanical loading, but little is known about the fundamental mechanisms that regulate tendon growth and remodeling in vivo. Data from cultured tendon fibroblasts indicated that the p38 MAPK pathway plays an important role in tendon fibroblast proliferation and collagen synthesis in vitro. To gain greater insight into the mechanisms of tendon growth, and explore the role of p38 MAPK signaling in this process, we tested the hypotheses that inducing plantaris tendon growth through the ablation of the synergist Achilles tendon would result in rapid expansion of a neotendon matrix surrounding the original tendon, and that treatment with the p38 MAPK inhibitor SB203580 would prevent this growth. Rats were treated with vehicle or SB203580, and subjected to synergist ablation by bilateral tenectomy of the Achilles tendon. Changes in histological and biochemical properties of plantaris tendons were analyzed 3, 7, or 28 days after overload, and comparisons were made to non-overloaded animals. By 28 days after overload, tendon mass had increased by 30% compared to non-overloaded samples, and cross-sectional area (CSA) increased by around 50%, with most of the change occurring in the neotendon. The expansion in CSA initially occurred through the synthesis of a hyaluronic acid rich matrix that was progressively replaced with mature collagen. Pericytes were present in areas of active tendon growth, but never in the original tendon ECM. Inhibition of p38 MAPK resulted in a profound decrease in IL6 expression, and had a modest effect on the expression of other ECM and cell proliferation genes, but had a negligible impact on overall tendon growth. The combined results from this study provided novel insights into tendon mechanobiology, and suggest that p38 MAPK signaling does not appear to be necessary for tendon growth in vivo. PMID:25768932

  4. Growth factor signaling to mTORC1 by amino acid–laden macropinosomes

    PubMed Central

    Yoshida, Sei; Pacitto, Regina; Yao, Yao; Inoki, Ken

    2015-01-01

    The rapid activation of the mechanistic target of rapamycin complex-1 (mTORC1) by growth factors is increased by extracellular amino acids through yet-undefined mechanisms of amino acid transfer into endolysosomes. Because the endocytic process of macropinocytosis concentrates extracellular solutes into endolysosomes and is increased in cells stimulated by growth factors or tumor-promoting phorbol esters, we analyzed its role in amino acid–dependent activation of mTORC1. Here, we show that growth factor-dependent activation of mTORC1 by amino acids, but not glucose, requires macropinocytosis. In murine bone marrow–derived macrophages and murine embryonic fibroblasts stimulated with their cognate growth factors or with phorbol myristate acetate, activation of mTORC1 required an Akt-independent vesicular pathway of amino acid delivery into endolysosomes, mediated by the actin cytoskeleton. Macropinocytosis delivered small, fluorescent fluid-phase solutes into endolysosomes sufficiently fast to explain growth factor–mediated signaling by amino acids. Therefore, the amino acid–laden macropinosome is an essential and discrete unit of growth factor receptor signaling to mTORC1. PMID:26438830

  5. Nodal and Lefty signaling regulates the growth of pancreatic cells

    PubMed Central

    Zhang, You-Qing; Sterling, Lori; Stotland, Aleksandr; Hua, Hong; Kritzik, Marcie; Sarvetnick, Nora

    2014-01-01

    Nodal and its antagonist, Lefty, are important mediators specifying the laterality of the organs during embryogenesis. Nodal signals through activin receptors in the presence of its co-receptor, Cripto. In the present study, we investigated the possible roles of Nodal and Lefty signaling during islet development and regeneration. We found that both Nodal and Lefty are expressed in the pancreas during embryogenesis and islet regeneration. In vitro studies demonstrated that Nodal inhibits, whereas Lefty enhances, the proliferation of a pancreatic cell line. In addition, we showed that Lefty-1 activates MAPK and Akt phosphorylation in these cells. In vivo blockade of endogenous Lefty using neutralizing Lefty-1 monoclonal antibody results in a significantly decreased proliferation of duct epithelial cells during islet regeneration. This is the first study to decipher the expression and function of Nodal and Lefty in pancreatic growth. Importantly, our results highlight a novel function of Nodal-Lefty signaling in the regulation of expansion of pancreatic cells. PMID:18393305

  6. Hair growth promoting effect of Zizyphus jujuba essential oil.

    PubMed

    Yoon, Jung In; Al-Reza, Sharif M; Kang, Sun Chul

    2010-05-01

    This study was undertaken to examine the efficacy of essential oil from seeds of Zizyphus jujuba for its potential role on hair growth by in vivo method. Essential oil was applied at different concentrations (0.1%, 1% and 10%) over the shaved skin onto the backs of BALB/c mice and monitored for 21 days. After 21 days, mice treated with 1% and 10% of oil produced a greater effect on the length of hair which were measured to be 9.96 and 10.02 mm, respectively, as compared to the control (8.94 mm). We measured the weight of hair/cm(2) area of dorsal skin and also evaluated hair thickness and hair follicles microscopically after plucking the hair immediately from the shaved area of mice and found the best results for 1% of essential oil-treated mice. From this study, it is concluded that Z. jujuba essential oil possesses hair growth promoting activity. PMID:20206225

  7. Promotion of hair growth by Rosmarinus officinalis leaf extract.

    PubMed

    Murata, Kazuya; Noguchi, Kazuma; Kondo, Masato; Onishi, Mariko; Watanabe, Naoko; Okamura, Katsumasa; Matsuda, Hideaki

    2013-02-01

    Topical administration of Rosmarinus officinalis leaf extract (RO-ext, 2 mg/day/mouse) improved hair regrowth in C57BL/6NCrSlc mice that experienced hair regrowth interruption induced by testosterone treatment. In addition, RO-ext promoted hair growth in C3H/He mice that had their dorsal areas shaved. To investigate the antiandrogenic activity mechanism of RO-ext, we focused on inhibition of testosterone 5α-reductase, which is well recognized as one of the most effective strategies for the treatment of androgenic alopecia. RO-ext showed inhibitory activity of 82.4% and 94.6% at 200 and 500 µg/mL, respectively. As an active constituent of 5α-reductase inhibition, 12-methoxycarnosic acid was identified with activity-guided fractionation. In addition, the extract of R. officinalis and 12-methoxycarnosic acid inhibited androgen-dependent proliferation of LNCaP cells as 64.5% and 66.7% at 5 µg/mL and 5 μM, respectively. These results suggest that they inhibit the binding of dihydrotestosterone to androgen receptors. Consequently, RO-ext is a promising crude drug for hair growth. PMID:22517595

  8. Bioprospecting glacial ice for plant growth promoting bacteria.

    PubMed

    Balcazar, Wilvis; Rondón, Johnma; Rengifo, Marcos; Ball, María M; Melfo, Alejandra; Gómez, Wileidy; Yarzábal, Luis Andrés

    2015-08-01

    Glaciers harbor a wide diversity of microorganisms, metabolically versatile, highly tolerant to multiple environmental stresses and potentially useful for biotechnological purposes. Among these, we hypothesized the presence of bacteria able to exhibit well-known plant growth promoting traits (PGP). These kinds of bacteria have been employed for the development of commercial biofertilizers; unfortunately, these biotechnological products have proven ineffective in colder climates, like the ones prevailing in mountainous ecosystems. In the present work, we prospected glacial ice collected from two small tropical glaciers, located above 4.900 m in the Venezuelan Andes, for cold-active PGP bacteria. The initial screening strategy allowed us to detect the best inorganic-P solubilizers at low temperatures, from a sub-sample of 50 bacterial isolates. Solubilization of tricalcium phosphate, aluminum- and iron-phosphate, occurred in liquid cultures at low temperatures and was dependent on medium acidification by gluconic acid production, when bacteria were supplied with an appropriate source of carbon. Besides, the isolates were psychrophilic and in some cases exhibited a broad range of growth-temperatures, from 4 °C to 30 °C. Additional PGP abilities, including phytohormone- and HCN production, siderophore excretion and inhibition of phytopathogens, were confirmed in vitro. Nucleotidic sequence analysis of 16S rRNA genes allowed us to place the isolates within the Pseudomonas genus. Our results support the possible use of these strains to develop cold-active biofertilizers to be used in mountainous agriculture. PMID:26211959

  9. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions

    PubMed Central

    Pedrosa, Ana-Rita; Trindade, Alexandre; Carvalho, Catarina; Graça, José; Carvalho, Sandra; Peleteiro, Maria C.; Adams, Ralf H.; Duarte, António

    2015-01-01

    Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development, which direct contribution to the regulation of tumor angiogenesis remains to be fully characterized. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). By modulating levels of endothelial Jag1, we observed that this ligand regulates tumor vessel density, branching, and perivascular maturation, thus affecting tumor vascular perfusion. The pro-angiogenic function is exerted by its ability to positively regulate levels of Vegfr-2 while negatively regulating Vegfr-1. Additionally, endothelial Jagged1 appears to exert an angiocrine function possibly by activating Notch3/Hey1 in tumor cells, promoting proliferation, survival and epithelial-to-mesenchymal transition (EMT), potentiating tumor development. These findings provide valuable mechanistic insights into the role of endothelial Jagged1 in promoting solid tumor development and support the notion that it may constitute a promising target for cancer therapy. PMID:26213336

  10. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions.

    PubMed

    Pedrosa, Ana-Rita; Trindade, Alexandre; Carvalho, Catarina; Graça, José; Carvalho, Sandra; Peleteiro, Maria C; Adams, Ralf H; Duarte, António

    2015-09-15

    Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development, which direct contribution to the regulation of tumor angiogenesis remains to be fully characterized. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). By modulating levels of endothelial Jag1, we observed that this ligand regulates tumor vessel density, branching, and perivascular maturation, thus affecting tumor vascular perfusion. The pro-angiogenic function is exerted by its ability to positively regulate levels of Vegfr-2 while negatively regulating Vegfr-1. Additionally, endothelial Jagged1 appears to exert an angiocrine function possibly by activating Notch3/Hey1 in tumor cells, promoting proliferation, survival and epithelial-to-mesenchymal transition (EMT), potentiating tumor development. These findings provide valuable mechanistic insights into the role of endothelial Jagged1 in promoting solid tumor development and support the notion that it may constitute a promising target for cancer therapy. PMID:26213336

  11. Hedgehog signaling in prostate epithelial-mesenchymal growth regulation

    PubMed Central

    Peng, Yu-Ching; Joyner, Alexandra L.

    2015-01-01

    The prostate gland plays an important role in male reproduction, and is also an organ prone to diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. The prostate consists of ducts with an inner layer of epithelium surrounded by stroma. Reciprocal signaling between these two cell compartments is instrumental to normal prostatic development, homeostasis, regeneration, as well as tumor formation. Hedgehog (HH) signaling is a master regulator in numerous developmental processes. In many organs, HH plays a key role in epithelial-mesenchymal signaling that regulates organ growth and tissue differentiation, and abnormal HH signaling has been implicated in the progression of various epithelial carcinomas. In this review, we focus on recent studies exploring the multipotency of endogenous postnatal and adult epithelial and stromal stem cells and studies addressing the role of HH in prostate development and cancer. We discuss the implications of the results for a new understanding of prostate development and disease. Insight into the cellular and molecular mechanisms underlying epithelial-mesenchymal growth regulation should provide a basis for devising innovative therapies to combat diseases of the prostate. PMID:25641695

  12. Early signaling dynamics of the epidermal growth factor receptor.

    PubMed

    Reddy, Raven J; Gajadhar, Aaron S; Swenson, Eric J; Rothenberg, Daniel A; Curran, Timothy G; White, Forest M

    2016-03-15

    Despite extensive study of the EGF receptor (EGFR) signaling network, the immediate posttranslational changes that occur in response to growth factor stimulation remain poorly characterized; as a result, the biological mechanisms underlying signaling initiation remain obscured. To address this deficiency, we have used a mass spectrometry-based approach to measure system-wide phosphorylation changes throughout the network with 10-s resolution in the 80 s after stimulation in response to a range of eight growth factor concentrations. Significant changes were observed on proteins far downstream in the network as early as 10 s after stimulation, indicating a system capable of transmitting information quickly. Meanwhile, canonical members of the EGFR signaling network fall into clusters with distinct activation patterns. Src homology 2 domain containing transforming protein (Shc) and phosphoinositol 3-kinase (PI3K) phosphorylation levels increase rapidly, but equilibrate within 20 s, whereas proteins such as Grb2-associated binder-1 (Gab1) and SH2-containing tyrosine phosphatase (SHP2) show slower, sustained increases. Proximity ligation assays reveal that Shc and Gab1 phosphorylation patterns are representative of separate timescales for physical association with the receptor. Inhibition of phosphatases with vanadate reveals site-specific regulatory mechanisms and also uncovers primed activating components in the network, including Src family kinases, whose inhibition affects only a subset of proteins within the network. The results presented highlight the complexity of signaling initiation and provide a window into exploring mechanistic hypotheses about receptor tyrosine kinase (RTK) biology. PMID:26929352

  13. Biomimetic scaffold combined with electrical stimulation and growth factor promotes tissue engineered cardiac development.

    PubMed

    Park, Hyoungshin; Larson, Benjamin L; Kolewe, Martin E; Vunjak-Novakovic, Gordana; Freed, Lisa E

    2014-02-15

    Toward developing biologically sound models for the study of heart regeneration and disease, we cultured heart cells on a biodegradable, microfabricated poly(glycerol sebacate) (PGS) scaffold designed with micro-structural features and anisotropic mechanical properties to promote cardiac-like tissue architecture. Using this biomimetic system, we studied individual and combined effects of supplemental insulin-like growth factor-1 (IGF-1) and electrical stimulation (ES). On culture day 8, all tissue constructs could be paced and expressed the cardiac protein troponin-T. IGF-1 reduced apoptosis, promoted cell-to-cell connectivity, and lowered excitation threshold, an index of electrophysiological activity. ES promoted formation of tissue-like bundles oriented in parallel to the electrical field and a more than ten-fold increase in matrix metalloprotease-2 (MMP-2) gene expression. The combination of IGF-1 and ES increased 2D projection length, an index of overall contraction strength, and enhanced expression of the gap junction protein connexin-43 and sarcomere development. This culture environment, designed to combine cardiac-like scaffold architecture and biomechanics with molecular and biophysical signals, enabled functional assembly of engineered heart muscle from dissociated cells and could serve as a template for future studies on the hierarchy of various signaling domains relative to cardiac tissue development. PMID:24240126

  14. Promotion of lung tumor growth by interleukin-17

    PubMed Central

    Xu, Beibei; Guenther, James F.; Pociask, Derek A.; Wang, Yu; Kolls, Jay K.; You, Zongbing; Chandrasekar, Bysani; Shan, Bin; Sullivan, Deborah E.

    2014-01-01

    Recent findings demonstrate that inhaled cigarette smoke, the predominant lung carcinogen, elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17A (IL-17), the hallmark cytokine of Th17 inflammation, displays pro- and antitumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor growth, we used an autochthonous tumor model (K-RasLA1 mice) with lung delivery of a recombinant adenovirus that expresses IL-17A. Virus-mediated expression of IL-17A in K-RasLA1 mice at 8–10 wk of age doubled lung tumor growth in 3 wk relative to littermates that received a green fluorescent protein-expressing control adenovirus. IL-17 induced matrix metalloproteinase-9 (MMP-9) expression in vivo and in vitro. In accord with this finding, selective and specific inhibitors of MMP-9 repressed the increased motility and invasiveness of IL-17-treated lung tumor cells in culture. Knockdown or mutation of p53 promoted the motility of murine lung tumor cells and abrogated the promigratory role of IL-17. Coexpression of siRNA-resistant wild-type, but not mutant, human p53 rescued both IL-17-mediated migration and MMP-9 mRNA induction in p53 knockdown lung tumor cells. IL-17 increased MMP-9 mRNA stability by reducing interaction with the mRNA destabilizing serine/arginine-rich splicing factor 1 (SRSF1). Taken together, our results indicate that IL-17 stimulates lung tumor growth and regulates MMP-9 mRNA levels in a p53- and SRSF1-dependent manner. PMID:25038189

  15. Targeting the Transforming Growth Factor-β Signaling Pathway in Human Cancer

    PubMed Central

    Nagaraj, Nagathihalli S

    2009-01-01

    The transforming growth factor-β (TGF-β) signaling pathway plays a pivotal role in diverse cellular processes. TGF-β switches its role from tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers. It is widely believed that Smad-dependent pathway is involved in TGF-β tumor suppressive functions, whereas activation of Smad-independent pathways coupled with the loss of tumor suppressor functions of TGF-β is important for its pro-oncogenic functions. TGF-β signaling has been considered as a very suitable therapeutic target. The discovery of oncogenic actions of TGF-β has generated a great deal of enthusiasm for developing TGF-β signaling inhibitors for the treatment of cancer. The challenge is to identify the group of patients where targeted tumors are not only refractory to TGF-β-induced tumor suppressor functions but also responsive to tumor promoting effects of TGF-β. TGF-β pathway inhibitors including small and large molecules have now entered clinical trials. Preclinical studies with these inhibitors have shown promise in a variety of different tumor models. Here we emphasize on the mechanisms of signaling and specific targets of the TGF-β pathway that are critical effectors of tumor progression and invasion. This report also focuses on the therapeutic intervention of TGF-β signaling in human cancers. PMID:20001556

  16. Paradox of plant growth promotion potential of rhizobacteria and their actual promotion effect on growth of barley (Hordeum vulgare L.) under salt stress.

    PubMed

    Cardinale, Massimiliano; Ratering, Stefan; Suarez, Christian; Zapata Montoya, Ana Maria; Geissler-Plaum, Rita; Schnell, Sylvia

    2015-12-01

    From the rhizosphere of two salt tolerant plant species, Hordeum secalinum and Plantago winteri growing in a naturally salt meadow, 100 strains were isolation on enrichment media for various plant growth-promoting (PGP) functions (ACC deaminase activity, auxin synthesis, calcium phosphate mobilization and nitrogen fixation). Based on the taxonomic affiliation of the isolated bacteria and their enrichment medium 22 isolates were selected to test their growth promotion effect on the crop barley (Hordeum vulgare) under salt stress in pot experiment. In parallel the isolates were characterized in pure culture for their plant growth-promoting activities. Surprisingly the best promotors did not display a promising set of PGP activities. Isolates with multiple PGP-activities in pure culture like Microbacterium natoriense strain E38 and Pseudomonas brassicacearum strain E8 did not promote plant growth. The most effective isolate was strain E108 identified as Curtobacterium flaccumfaciens, which increased barley growth up to 300%. In pure culture strain E108 showed only two out of six plant growth promoting activities and would have been neglected. Our results highlight that screening based on pure culture assays may not be suitable for recognition of best plant growth promotion candidates and could preclude the detection of both new PGPR and new plant promotion mechanisms. PMID:26640049

  17. Melanoma NOS1 expression promotes dysfunctional IFN signaling

    PubMed Central

    Liu, Qiuzhen; Tomei, Sara; Ascierto, Maria Libera; De Giorgi, Valeria; Bedognetti, Davide; Dai, Cuilian; Uccellini, Lorenzo; Spivey, Tara; Pos, Zoltan; Thomas, Jaime; Reinboth, Jennifer; Murtas, Daniela; Zhang, Qianbing; Chouchane, Lotfi; Weiss, Geoffrey R.; Slingluff, Craig L.; Lee, Peter P.; Rosenberg, Steven A.; Alter, Harvey; Yao, Kaitai; Wang, Ena; Marincola, Francesco M.

    2014-01-01

    In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells. PMID:24691438

  18. Analysis of Volatile Organic Compounds Emitted by Plant Growth-Promoting Fungus Phoma sp. GS8-3 for Growth Promotion Effects on Tobacco

    PubMed Central

    Naznin, Hushna Ara; Kimura, Minako; Miyazawa, Mitsuo; Hyakumachi, Mitsuro

    2013-01-01

    We extracted volatile organic compounds (VOCs) emitted by a plant growth-promoting fungus (PGPF) Phoma sp. GS8-3 by gas chromatography and identified them by mass spectrometry. All of the identified compounds belonged to C4-C8 hydrocarbons. Volatiles varied in number and quantity by the culture period of the fungus (in days). 2-Methyl-propanol and 3-methyl-butanol formed the main components of the volatile blends for all the culture periods of fungus. Growth-promoting effects of the identified synthetic compounds were analyzed individually and in blends using tobacco plants. We found that the mixture of volatiles extracted from 3-day-old culture showed significant growth promotion in tobacco in vitro. The volatile blend showed better growth promotion at lower than higher concentrations. Our results confirm the potential role of volatile organic compounds in the mechanism of growth enhancement by GS8-3. PMID:23080408

  19. Redox signaling in the growth and development of colonial hydroids.

    PubMed

    Blackstone, Neil W

    2003-02-01

    Redox signaling provides a quick and efficient mechanism for clonal or colonial organisms to adapt their growth and development to aspects of the environment, e.g. the food supply. A 'signature' of mitochondrial redox signaling, particularly as mediated by reactive oxygen species (ROS), can be elucidated by experimental manipulation of the electron transport chain. The major sites of ROS formation are found at NADH dehydrogenase of complex I and at the interface between coenzyme Q and complex III. Inhibitors of complex III should thus upregulate ROS from both sites; inhibitors of complex I should upregulate ROS from the first but not the second site, while uncouplers of oxidative phosphorylation should downregulate ROS from both sites. To investigate the possibility of such redox signaling, perturbations of colony growth and development were carried out using the hydroid Podocoryna carnea. Oxygen uptake of colonies was measured to determine comparable physiological doses of antimycin A(1) (an inhibitor of complex III), rotenone (an inhibitor of complex I) and carbonyl cyanide m-chlorophenylhydrazone (CCCP; an uncoupler of oxidative phosphorylation). Using these doses, clear effects on colony growth and development were obtained. Treatment with antimycin A(1) results in 'runner-like' colony growth, with widely spaced polyps and stolon branches, while treatment with CCCP results in 'sheet-like' growth, with closely spaced polyps and stolon branches. Parallel results have been obtained previously with azide, an inhibitor of complex IV, and dinitrophenol, another uncoupler of oxidative phosphorylation. Perhaps surprisingly, rotenone produced effects on colony development similar to those of CCCP. Assays of peroxides using 2',7'-dichlorofluorescin diacetate and fluorescent microscopy suggest a moderate difference in ROS formation between the antimycin and rotenone treatments. The second site of ROS formation (the interface between coenzyme Q and complex III) may thus

  20. Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-β signaling.

    PubMed

    Tian, Yao; Yu, Yue; Hou, Li-Kun; Chi, Jiang-Rui; Mao, Jie-Fei; Xia, Li; Wang, Xin; Wang, Ping; Cao, Xu-Chen

    2016-03-01

    Serum deprivation response (SDPR), a key substrate for protein kinase C, play a critical role in inducing membrane curvature and participate in the formation of caveolae. However, the function of SDPR in cancer development and progression is still not clear. Here, we found that SDPR is downregulated in human breast cancer. Overexpression of SDPR suppresses cell proliferation and invasion in MDA-MB-231 cells, while depletion of SDPR promotes cell proliferation and invasion in MCF10A cells. Subsequently, SDPR depletion induces epithelial-mesenchymal transition (EMT)-like phenotype. Finally, knockdown of SDPR activates transforming growth factor-β (TGF-β) signaling by upregulation of TGF-β1 expression. In conclusion, our results showed that SDPR inhibits breast cancer progression by blocking TGF-β signaling. Serum deprivation response suppresses cell proliferation and invasion in breast cancer cells. SDPR depletion induces epithelial-mesenchymal transition by activation of TGF-β signaling. PMID:26749136

  1. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment.

    PubMed

    Tai, Yu-Tzu; Acharya, Chirag; An, Gang; Moschetta, Michele; Zhong, Mike Y; Feng, Xiaoyan; Cea, Michele; Cagnetta, Antonia; Wen, Kenneth; van Eenennaam, Hans; van Elsas, Andrea; Qiu, Lugui; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C

    2016-06-23

    Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM. PMID:27127303

  2. Promoted growth of murine hair follicles through controlled release of vascular endothelial growth factor.

    PubMed

    Ozeki, Makoto; Tabata, Yasuhiko

    2002-06-01

    The objective of this study is to investigate whether or not the controlled release of vascular endothelial growth factor (VEGF) is effective in promoting the hair follicle growth of mice in second anagen of hair cycle. VEGF was incorporated into a biodegradable collagen hydrogel for its controlled release. Following implantation of the collagen hydrogel incorporating 0 or 2 microg of VEGF and injection of 0 or 2 microg of VEGF in the solution form into the back subcutis of mice, the hair follicle growth was evaluated photometrically and histologically in terms of the skin color of reverse side of the implanted or injected site, the skin thickness, and the area occupied by hair follicle tissue. Ten days later, the skin color of mice implanted with the collagen hydrogel incorporating 2 microg of VEGF was significantly darker than that injected with 2 pg of VEGF. The collagen hydrogel incorporating VEGF increased the hair follicle area at the implanted site to a significantly greater extent than other agents while significant angiogenetic effect in the skin tissue was observed. VEGF-free, empty collagen hydrogels did not affect the skin darkness, hair follicle growth, and the angiogenesis. Moreover, the hair shaft length was significantly elongated by the collagen hydrogel incorporating VEGF, in marked contrast to other agents. Immunohistolchemicalstaining with proliferating cell nuclear antigen revealed that the collagen hydrogel incorporating VEGF promoted the proliferation of cells around the hair follicle more frequently than free VEGF. We concluded that the controlled release of VEGF more positively acted on the hair growth cycle of mice for hair growth than the injection of free VEGF. PMID:12013184

  3. EGFR/MDM2 signaling promotes NF-κB activation via PPARγ degradation.

    PubMed

    Xu, Ying; Jin, Jianhua; Zhang, Wenbo; Zhang, Zhi; Gao, Jiaming; Liu, Qian; Zhou, Chenglin; Xu, Qinggang; Shi, Haifeng; Hou, Yongzhong; Shi, Juanjuan

    2016-02-01

    Dysregulated expression of epidermal growth factor receptor (EGFR) has been implicated in many cancer events, while peroxisome proliferator-activated receptor γ (PPARγ) negatively regulates cancer progression. The molecular mechanism of EGFR interaction with PPARγ is still unclear. Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase. PPARγ degradation by EGFR/MDM2 signaling resulted in accumulation of nuclear factor-kappaB (NF-κB)/p65 protein levels and increasing NF-κB activation. In contrast, PPARγ-Y74A mutant reversed this event. Moreover, PPARγ-Y74A mutant suppressed cell proliferation and increased chemotherapeutic agent-induced cancer cell sensitivity. Importantly, the clinical findings show that the nuclear phosphorylation of PPARγ-Y74 and EGFR expression in colonic cancer tissues was higher than that in control normal tissues. Thus, our study revealed a novel molecular mechanism that nuclear EGFR/NF-κB signaling promoted cell proliferation by destructing PPARγ function, which provides a novel strategy for cancer treatment. PMID:26718225

  4. Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth.

    PubMed

    Dhayade, Sandeep; Kaesler, Susanne; Sinnberg, Tobias; Dobrowinski, Hyazinth; Peters, Stefanie; Naumann, Ulrike; Liu, He; Hunger, Robert E; Thunemann, Martin; Biedermann, Tilo; Schittek, Birgit; Simon, Hans-Uwe; Feil, Susanne; Feil, Robert

    2016-03-22

    Sildenafil, an inhibitor of the cGMP-degrading phosphodiesterase 5 that is used to treat erectile dysfunction, has been linked to an increased risk of melanoma. Here, we have examined the potential connection between cGMP-dependent signaling cascades and melanoma growth. Using a combination of biochemical assays and real-time monitoring of melanoma cells, we report a cGMP-dependent growth-promoting pathway in murine and human melanoma cells. We document that C-type natriuretic peptide (CNP), a ligand of the membrane-bound guanylate cyclase B, enhances the activity of cGMP-dependent protein kinase I (cGKI) in melanoma cells by increasing the intracellular levels of cGMP. Activation of this cGMP pathway promotes melanoma cell growth and migration in a p44/42 MAPK-dependent manner. Sildenafil treatment further increases intracellular cGMP concentrations, potentiating activation of this pathway. Collectively, our data identify this cGMP-cGKI pathway as the link between sildenafil usage and increased melanoma risk. PMID:26971999

  5. Dragon (repulsive guidance molecule b, RGMb) is a novel gene that promotes colorectal cancer growth

    PubMed Central

    Shi, Ying; Chen, Guo-Bin; Huang, Xiao-Xiao; Xiao, Chuan-Xing; Wang, Huan-Huan; Li, Ye-Sen; Zhang, Jin-Fang; Li, Shao; Xia, Yin; Ren, Jian-Lin; Guleng, Bayasi

    2015-01-01

    Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer death. However, the molecular mechanisms underlying CRC initiation, growth and metastasis are poorly understood. Dragon (RGMb), a member of the repulsive guidance molecule (RGM) family, has been recently identified as a co-receptor for bone morphogenetic protein (BMP) signaling, but the role of Dragon in CRC development is undefined. Here, we show that Dragon expression was increased in colon cancer tissues compared to control tissues in CAC mouse model and in human patients. Dragon promoted proliferation of CT26.WT and CMT93 colon cancer cells and accelerated tumor growth in the xenograft mouse model. Dragon's action on colon cancer development was mediated via the BMP4-Smad1/5/8 and Erk1/2 pathways. Therefore, our results have revealed that Dragon is a novel gene that promotes CRC growth through the BMP pathway. Dragon may be exploited as a potential therapeutic target for CRC treatment. PMID:26029998

  6. RHOA inactivation enhances Wnt signaling and promotes colorectal cancer

    PubMed Central

    Rodrigues, Paulo; Macaya, Irati; Bazzocco, Sarah; Mazzolini, Rocco; Andretta, Elena; Dopeso, Higinio; Mateo-Lozano, Silvia; Bilić, Josipa; Cartón-García, Fernando; Nieto, Rocio; Suárez-López, Lucia; Afonso, Elsa; Landolfi, Stefania; Hernandez-Losa, Javier; Kobayashi, Kazuto; Cajal, Santiago Ramón y; Tabernero, Josep; Tebbutt, Niall C.; Mariadason, John M.; Schwartz, Simo; Arango, Diego

    2014-01-01

    Activation of the small GTPase RHOA has strong oncogenic effects in many tumor types, although its role in colorectal cancer remains unclear. Here we show that RHOA inactivation contributes to colorectal cancer progression/metastasis, largely through the activation of Wnt/β-catenin signaling. RhoA inactivation in the murine intestine accelerates the tumorigenic process and in human colon cancer cells leads to the redistribution of β-catenin from the membrane to the nucleus and enhanced Wnt/β-catenin signaling, resulting in increased proliferation, invasion and de-differentiation. In mice, RHOA inactivation contributes to colon cancer metastasis and reduced RHOA levels were observed at metastatic sites compared to primary human colon tumors. Therefore, we have identified a new mechanism of activation of Wnt/β-catenin signaling and characterized the role of RHOA as a novel tumor suppressor in colorectal cancer. These results constitute a shift from the current paradigm and demonstrate that RHO GTPases can suppress tumor progression and metastasis. PMID:25413277

  7. Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma.

    PubMed

    Doucette, Tiffany A; Kong, Ling-Yuan; Yang, Yuhui; Ferguson, Sherise D; Yang, Jinbo; Wei, Jun; Qiao, Wei; Fuller, Gregory N; Bhat, Krishna P; Aldape, Kenneth; Priebe, Waldemar; Bögler, Oliver; Heimberger, Amy B; Rao, Ganesh

    2012-09-01

    Signal transducer and activator of transcription (STAT) 3 has been described as a "master regulator" of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target. PMID:22753228

  8. Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma

    PubMed Central

    Doucette, Tiffany A.; Kong, Ling-Yuan; Yang, Yuhui; Ferguson, Sherise D.; Yang, Jinbo; Wei, Jun; Qiao, Wei; Fuller, Gregory N.; Bhat, Krishna P.; Aldape, Kenneth; Priebe, Waldemar; Bögler, Oliver; Heimberger, Amy B.; Rao, Ganesh

    2012-01-01

    Signal transducer and activator of transcription (STAT) 3 has been described as a “master regulator” of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target. PMID:22753228

  9. Teneurin-4 promotes cellular protrusion formation and neurite outgrowth through focal adhesion kinase signaling

    PubMed Central

    Suzuki, Nobuharu; Numakawa, Tadahiro; Chou, Joshua; de Vega, Susana; Mizuniwa, Chihiro; Sekimoto, Kaori; Adachi, Naoki; Kunugi, Hiroshi; Arikawa-Hirasawa, Eri; Yamada, Yoshihiko; Akazawa, Chihiro

    2014-01-01

    Teneurin-4 (Ten-4), a transmembrane protein, is highly expressed in the central nervous system; however, its cellular and molecular function in neuronal differentiation remains unknown. In this study, we aimed to elucidate the function of Ten-4 in neurite outgrowth. Ten-4 expression was induced during neurite outgrowth of the neuroblastoma cell line Neuro-2a. Ten-4 protein was localized at the neurite growth cones. Knockdown of Ten-4 expression in Neuro-2a cells decreased the formation of the filopodia-like protrusions and the length of individual neurites. Conversely, overexpression of Ten-4 promoted filopodia-like protrusion formation. In addition, knockdown and overexpression of Ten-4 reduced and elevated the activation of focal adhesion kinase (FAK) and Rho-family small GTPases, Cdc42 and Rac1, key molecules for the membranous protrusion formation downstream of FAK, respectively. Inhibition of the activation of FAK and neural Wiskott-Aldrich syndrome protein (N-WASP), which is a downstream regulator of FAK and Cdc42, blocked protrusion formation by Ten-4 overexpression. Further, Ten-4 colocalized with phosphorylated FAK in the filopodia-like protrusion regions. Together, our findings show that Ten-4 is a novel positive regulator of cellular protrusion formation and neurite outgrowth through the FAK signaling pathway.—Suzuki, N., Numakawa, T., Chou, J., de Vega, S., Mizuniwa, C., Sekimoto, K., Adachi, N., Kunugi, H., Arikawa-Hirasawa, E., Yamada, Y., Akazawa, C. Teneurin-4 promotes cellular protrusion formation and neurite outgrowth through focal adhesion kinase signaling. PMID:24344332

  10. SNF2H promotes hepatocellular carcinoma proliferation by activating the Wnt/β-catenin signaling pathway

    PubMed Central

    Wang, Yanan; Qin, Juanxiu; Liu, Qian; Hong, Xufen; Li, Tianming; Zhu, Yuanjun; He, Lei; Zheng, Bing; Li, Min

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. Surgical resection is always inapplicable to HCC patients diagnosed at an advanced tumor stage. The mechanisms underlying HCC cell proliferation remain obscure. In the present study, SWItch/sucrose nonfermentable catalytic subunit SNF2 (SNF2H) expression was tested in HCC tissues and Wnt/β-catenin pathway activation upon overexpression of SNF2H or knockdown of SNF2H expression was investigated in cultured HCC cells. It was demonstrated that SNF2H is a vital factor for HCC growth. The SNF2H expression level is increased in HCC tissues compared with paratumoral liver tissues. SNF2H promotes HCC cell proliferation and colony formation ability in vitro. SNF2H may increase the protein level of β-catenin and enhance its nuclear accumulation in HCC cells, thereby leading to the activation of the Wnt/β-catenin signaling pathway. In conclusion, the present results indicate that SNF2H plays a vital role in HCC cell growth, suggesting that SNF2H may be a promising therapeutic target for HCC treatment. PMID:27446433

  11. Interbacterial signaling via Burkholderia contact-dependent growth inhibition system proteins.

    PubMed

    Garcia, Erin C; Perault, Andrew I; Marlatt, Sara A; Cotter, Peggy A

    2016-07-19

    In prokaryotes and eukaryotes, cell-cell communication and recognition of self are critical to coordinate multicellular functions. Although kin and kind discrimination are increasingly appreciated to shape naturally occurring microbe populations, the underlying mechanisms that govern these interbacterial interactions are insufficiently understood. Here, we identify a mechanism of interbacterial signal transduction that is mediated by contact-dependent growth inhibition (CDI) system proteins. CDI systems have been characterized by their ability to deliver a polymorphic protein toxin into the cytoplasm of a neighboring bacterium, resulting in growth inhibition or death unless the recipient bacterium produces a corresponding immunity protein. Using the model organism Burkholderia thailandensis, we show that delivery of a catalytically active CDI system toxin to immune (self) bacteria results in gene expression and phenotypic changes within the recipient cells. Termed contact-dependent signaling (CDS), this response promotes biofilm formation and other community-associated behaviors. Engineered strains that are isogenic with B. thailandensis, except the DNA region encoding the toxin and immunity proteins, did not display CDS, whereas a strain of Burkholderia dolosa producing a nearly identical toxin-immunity pair induced signaling in B. thailandensis Our data indicate that bcpAIOB loci confer dual benefits; they direct antagonism toward non-self bacteria and promote cooperation between self bacteria, with self being defined by the bcpAIOB allele and not by genealogic relatedness. PMID:27335458

  12. Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

    SciTech Connect

    Fukumoto, Yasunori Kuki, Kazumasa; Morii, Mariko; Miura, Takahito; Honda, Takuya; Ishibashi, Kenichi; Hasegawa, Hitomi; Kubota, Sho; Ide, Yudai; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

    2014-09-26

    Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint.

  13. Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation.

    PubMed

    Bennett, Darin C; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K K; McElwee, Kevin J; Cheng, Kimberly M

    2015-09-01

    Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51×faster), ostrich oil (1.46×faster), and rhea oil (1.64×faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35×slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions. PMID:26217022

  14. Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation

    PubMed Central

    Bennett, Darin C.; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K. K.; McElwee, Kevin J.; Cheng, Kimberly M.

    2015-01-01

    Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51 × faster), ostrich oil (1.46 × faster), and rhea oil (1.64 × faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35 × slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions. PMID:26217022

  15. Alkamides Isolated from Plants Promote Growth and Alter Root Development in Arabidopsis1

    PubMed Central

    Ramírez-Chávez, Enrique; López-Bucio, José; Herrera-Estrella, Luis; Molina-Torres, Jorge

    2004-01-01

    To date, several classes of hormones have been described that influence plant development, including auxins, cytokinins, ethylene, and, more recently, brassinosteroids. However, it is known that many fungal and bacterial species produce substances that alter plant growth that, if naturally present in plants, might represent novel classes of plant growth regulators. Alkamides are metabolites widely distributed in plants with a broad range of biological activities. In this work, we investigated the effects of affinin, an alkamide naturally occurring in plants, and its derivates, N-isobutyl-2E-decenamide and N-isobutyl-decanamide, on plant growth and early root development in Arabidopsis. We found that treatments with affinin in the range of 10-6 to 10-4 m alter shoot and root biomass production. This effect correlated with alteration on primary root growth, lateral root formation, and root hair elongation. Low concentrations of affinin (7 × 10-6–2.8 × 10-5 m) enhanced primary root growth and root hair elongation, whereas higher concentrations inhibited primary root growth that related with a reduction in cell proliferating activity and cell elongation. N-isobutyl-2E-decenamide and N-isobutyl-decanamide were found to stimulate root hair elongation at concentrations between 10-8 to 10-7 m. Although the effects of alkamides were similar to those produced by auxins on root growth and cell parameters, the ability of the root system to respond to affinin was found to be independent of auxin signaling. Our results suggest that alkamides may represent a new group of plant growth promoting substances with significant impact on root development and opens the possibility of using these compounds for improved plant production. PMID:14988477

  16. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions.

    PubMed

    Ilangumaran, Subburaj; Villalobos-Hernandez, Alberto; Bobbala, Diwakar; Ramanathan, Sheela

    2016-06-01

    Hepatocyte growth factor (HGF) signaling via the MET receptor is essential for embryonic development and tissue repair. On the other hand, deregulated MET signaling promotes tumor progression in diverse types of cancers. Even though oncogenic MET signaling remains the major research focus, the HGF-MET axis has also been implicated in diverse aspects of immune cell development and functions. In the presence of other hematopoietic growth factors, HGF promotes the development of erythroid, myeloid and lymphoid lineage cells and thrombocytes. In monocytes and macrophages responding to inflammatory stimuli, induction of autocrine HGF-MET signaling can contribute to tissue repair via stimulating anti-inflammatory cytokine production. HGF-MET signaling can also modulate adaptive immune response by facilitating the migration of Langerhans cells and dendritic cells to draining lymph nodes. However, MET signaling has also been shown to induce tolerogenic dendritic cells in mouse models of graft-versus-host disease and experimental autoimmune encephalomyelitis. HGF-MET axis is also implicated in promoting thymopoiesis and the survival and migration of B lymphocytes. Recent studies have shown that MET signaling induces cardiotropism in activated T lymphocytes. Further understanding of the HGF-MET axis in the immune system would allow its therapeutic manipulation to improve immune cell reconstitution, restore immune homeostasis and to treat immuno-inflammatory diseases. PMID:26822708

  17. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.

    PubMed

    Kleffel, Sonja; Posch, Christian; Barthel, Steven R; Mueller, Hansgeorg; Schlapbach, Christoph; Guenova, Emmanuella; Elco, Christopher P; Lee, Nayoung; Juneja, Vikram R; Zhan, Qian; Lian, Christine G; Thomi, Rahel; Hoetzenecker, Wolfram; Cozzio, Antonio; Dummer, Reinhard; Mihm, Martin C; Flaherty, Keith T; Frank, Markus H; Murphy, George F; Sharpe, Arlene H; Kupper, Thomas S; Schatton, Tobias

    2015-09-10

    Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy. PMID:26359984

  18. Blocking Fibroblast Growth Factor Receptor Signaling Inhibits Tumor Growth, Lymphangiogenesis, and Metastasis

    PubMed Central

    Larrieu-Lahargue, Frédéric; Welm, Alana L.; Bouchecareilh, Marion; Alitalo, Kari; Li, Dean Y.; Bikfalvi, Andreas; Auguste, Patrick

    2012-01-01

    Fibroblast Growth Factor receptor (FGFR) activity plays crucial roles in tumor growth and patient survival. However, FGF (Fibroblast Growth Factor) signaling as a target for cancer therapy has been under-investigated compared to other receptor tyrosine kinases. Here, we studied the effect of FGFR signaling inhibition on tumor growth, metastasis and lymphangiogenesis by expressing a dominant negative FGFR (FGFR-2DN) in an orthotopic mouse mammary 66c14 carcinoma model. We show that FGFR-2DN-expressing 66c14 cells proliferate in vitro slower than controls. 66c14 tumor outgrowth and lung metastatic foci are reduced in mice implanted with FGFR-2DN-expressing cells, which also exhibited better overall survival. We found 66c14 cells in the lumen of tumor lymphatic vessels and in lymph nodes. FGFR-2DN-expressing tumors exhibited a decrease in VEGFR-3 (Vascular Endothelial Growth Factor Receptor-3) or podoplanin-positive lymphatic vessels, an increase in isolated intratumoral lymphatic endothelial cells and a reduction in VEGF-C (Vascular Endothelial Growth Factor-C) mRNA expression. FGFs may act in an autocrine manner as the inhibition of FGFR signaling in tumor cells suppresses VEGF-C expression in a COX-2 (cyclooxygenase-2) or HIF1-α (hypoxia-inducible factor-1 α) independent manner. FGFs may also act in a paracrine manner on tumor lymphatics by inducing expression of pro-lymphangiogenic molecules such as VEGFR-3, integrin α9, prox1 and netrin-1. Finally, in vitro lymphangiogenesis is impeded in the presence of FGFR-2DN 66c14 cells. These data confirm that both FGF and VEGF signaling are necessary for the maintenance of vascular morphogenesis and provide evidence that targeting FGFR signaling may be an interesting approach to inhibit tumor lymphangiogenesis and metastatic spread. PMID:22761819

  19. Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma.

    PubMed

    Andersen, Nicholas J; Nickoloff, Brian J; Dykema, Karl J; Boguslawski, Elissa A; Krivochenitser, Roman I; Froman, Roe E; Dawes, Michelle J; Baker, Laurence H; Thomas, Dafydd G; Kamstock, Debra A; Kitchell, Barbara E; Furge, Kyle A; Duesbery, Nicholas S

    2013-09-01

    Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal-regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease. PMID:23804705

  20. Nuclear PI3K signaling in cell growth and tumorigenesis

    PubMed Central

    Davis, William J.; Lehmann, Peter Z.; Li, Weimin

    2015-01-01

    The PI3K/Akt signaling pathway is a major driving force in a variety of cellular functions. Dysregulation of this pathway has been implicated in many human diseases including cancer. While the activity of the cytoplasmic PI3K/Akt pathway has been extensively studied, the functions of these molecules and their effector proteins within the nucleus are poorly understood. Harboring key cellular processes such as DNA replication and repair as well as nascent messenger RNA transcription, the nucleus provides a unique compartmental environment for protein–protein and protein–DNA/RNA interactions required for cell survival, growth, and proliferation. Here we summarize recent advances made toward elucidating the nuclear PI3K/Akt signaling cascade and its key components within the nucleus as they pertain to cell growth and tumorigenesis. This review covers the spatial and temporal localization of the major nuclear kinases having PI3K activities and the counteracting phosphatases as well as the role of nuclear PI3K/Akt signaling in mRNA processing and exportation, DNA replication and repair, ribosome biogenesis, cell survival, and tumorigenesis. PMID:25918701

  1. Response of intestinal microbiota to antibiotic growth promoters in chickens.

    PubMed

    Lin, Jun; Hunkapiller, Andree A; Layton, Alice C; Chang, Yun-Juan; Robbins, Kelly R

    2013-04-01

    Antibiotic growth promoters (AGPs) have been used as feed additives to improve average daily weight gain and feed efficiency in food animals for more than five decades. However, use of AGPs is associated with the emergence of antibiotic-resistant human pathogens of animal origin, posing a significant threat to food safety and public health. Thus, development of novel alternatives to AGPs is important to mitigate antimicrobial resistance in foodborne pathogens. To achieve this goal, the mode of action of AGPs should be elucidated. In this study, the response of the chicken gut microbiota to AGPs was examined using two culture-independent approaches: phospholipid fatty acid (PLFA) biomarker analysis and 16S rDNA clone library sequencing. PLFA analysis showed that AGP tylosin treatment changed composition of the microbiota in various intestinal sites; however, total viable bacterial biomass in intestine was not affected by tylosin treatment. PLFA analysis also revealed an abundant viable fungal population in chicken microbiota. Eight 16S rDNA libraries (96 clones per library) were constructed using ileal samples from chickens that received either antibiotic-free or medicated feed. The 16S rDNA clone analysis of the growth-relevant samples showed the AGP treatment influenced the diversity of ileum microbiota in the chickens primarily in the Firmicutes division. In particular, Lactobacillus spp. populations in the ileum of AGP-treated chickens were significantly lower than those from chickens receiving antibiotic-free feed. Together, this study revealed novel features of the intestinal microbiota in response to AGP treatment and suggested approach to develop potential alternatives to AGPs for mitigation of antimicrobial resistance in foodborne pathogens. PMID:23461609

  2. GENETIC MODIFICATION OF GIBBERELLIC ACID SIGNALING TO PROMOTE CARBON SEQUESTRATION IN TREE ROOTS AND STEMS

    SciTech Connect

    Busov, Victor

    2013-03-05

    Semidwarfism has been used extensively in row crops and horticulture to promote yield, reduce lodging, and improve harvest index, and it might have similar benefits for trees for short-rotation forestry or energy plantations, reclamation, phytoremediation, or other applications. We studied the effects of the dominant semidwarfism transgenes GA Insensitive (GAI) and Repressor of GAI-Like, which affect gibberellin (GA) action, and the GA catabolic gene, GA 2-oxidase, in nursery beds and in 2-year-old high-density stands of hybrid poplar (Populus tremula - Populus alba). Twenty-nine traits were analyzed, including measures of growth, morphology, and physiology. Endogenous GA levels were modified in most transgenic events; GA(20) and GA(8), in particular, had strong inverse associations with tree height. Nearly all measured traits varied significantly among genotypes, and several traits interacted with planting density, including aboveground biomass, root-shoot ratio, root fraction, branch angle, and crown depth. Semidwarfism promoted biomass allocation to roots over shoots and substantially increased rooting efficiency with most genes tested. The increased root proportion and increased leaf chlorophyll levels were associated with changes in leaf carbon isotope discrimination, indicating altered water use efficiency. Semidwarf trees had dramatically reduced growth when in direct competition with wild-type trees, supporting the hypothesis that semidwarfism genes could be effective tools to mitigate the spread of exotic, hybrid, and transgenic plants in wild and feral populations. We modified gibberellin (GA) metabolism and signaling in transgenic poplars using dominant transgenes and studied their effects for 3 years under field conditions. The transgenes that we employed either reduced the bioactive GAs, or attenuated their signaling. The majority of transgenic trees had significant and in many cases dramatic changes in height, crown architecture, foliage morphology

  3. RFPL3 and CBP synergistically upregulate hTERT activity and promote lung cancer growth

    PubMed Central

    Yu, Wendan; Cai, Xin; Dai, Meng; Xu, Tingting; Huang, Wenlin; Guo, Wei; Deng, Wuguo; Wu, Taihua

    2015-01-01

    hTERT is the key component of telomerase and its overactivation contributes to maintaining telomere length and cell immortalization. Previously, we identified RFPL3 as a new transcription activator of hTERT in lung cancers. However, the exact mechanism of RFPL3 in mediating hTERT activation and its associated signal regulatory network remain unclear. In this study, we found that RFPL3 colocalized and interacted directly with CBP in the nucleus of lung cancer cells. Immunohistochemical analysis of tissue microarrays of lung cancers revealed the simultaneous overexpression of both RFPL3 and CBP predicted relatively poor prognosis. Furthermore, we confirmed their synergistic stimulation on hTERT expression and tumor cell growth. The binding of RFPL3 to hTERT promoter was reduced markedly when CBP was knocked down by its specific siRNA or suppressed by its inhibitor in lung cancer cells with stable overexpression of RFPL3. When one of the two proteins RFPL3 and CBP was upregulated or downregulated, whereas the another remains unchanged, hTERT expression and telomerase activity were activated or repressed accordingly. In the meantime, the growth of lung cancer cells was also promoted or attenuated accordingly. Furthermore, we also found that RFPL3 coordinated with CBP to upregulate hTERT through the CBP-induced acetylation of RFPL3 protein and their co-anchoring at hTERT promoter region. Collectively, our results reveal a new mechanism of hTERT regulation in lung cancer cells and suggest the RFPL3/CBP/hTERT signaling pathway may be a new targets for lung cancer treatment. PMID:26318425

  4. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Changtao; Xie, Cen; Li, Fei; Zhang, Limin; Nichols, Robert G.; Krausz, Kristopher W.; Cai, Jingwei; Qi, Yunpeng; Fang, Zhong-Ze; Takahashi, Shogo; Tanaka, Naoki; Desai, Dhimant; Amin, Shantu G.; Albert, Istvan; Patterson, Andrew D.; Gonzalez, Frank J.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet–induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota–associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment. PMID:25500885

  5. mTORC1 Signaling Promotes Osteoblast Differentiation from Preosteoblasts

    PubMed Central

    Chen, Jianquan; Long, Fanxin

    2015-01-01

    Preosteoblasts are precursor cells that are committed to the osteoblast lineage. Differentiation of these cells to mature osteoblasts is regulated by the extracellular factors and environmental cues. Recent studies have implicated mTOR signaling in the regulation of osteoblast differentiation. However, mTOR exists in two distinct protein complexes (mTORC1 and mTORC2), and the specific role of mTORC1 in regulating the progression of preosteoblasts to mature osteoblastis still unclear. In this study, we first deleted Raptor, a unique and essential component of mTORC1, in primary calvarial cells. Deletion of Raptor resulted in loss of mTORC1 but an increase in mTORC2 signaling without overtly affecting autophagy. Under the osteogenic culture condition, Raptor-deficient cells exhibited a decrease in matrix synthesis and mineralization. qPCR analyses revealed that deletion of Raptor reduced the expression of late-stage markers for osteoblast differentiation (Bglap, Ibsp, and Col1a), while slightly increasing early osteoblast markers (Runx2, Sp7, and Alpl). Consistent with the findings in vitro, genetic ablation of Raptor in osterix-expressing cells led to osteopenia in mice. Together, our findings have identified a specific role for mTORC1 in the transition from preosteoblasts to mature osteoblasts. PMID:26090674

  6. Effects of anticoccidial and antibiotic growth promoter programs on broiler performance and immune status

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study investigated the effects of various coccidiosis control programs in combination with antibiotic growth promoters (AGPs) on growth performance and host immune responses in broiler chickens. The coccidiosis programs that were investigated include in ovo coccidiosis vaccination (CVAC) with ...

  7. Seed biopriming with plant growth promoting rhizobacteria: a review.

    PubMed

    Mahmood, Ahmad; Turgay, Oğuz Can; Farooq, Muhammad; Hayat, Rifat

    2016-08-01

    Beneficial microbes are applied to the soil and plant tissues directly or through seed inoculation, whereas soil application is preferred when there is risk of inhibitors or antagonistic microbes on the plant tissues. Insufficient survival of the microorganisms, hindrance in application of fungicides to the seeds and exposure to heat and sunlight in subsequent seed storage in conventional inoculation methods force to explore appropriate and efficient bacterial application method. Seed priming, where seeds are hydrated to activate metabolism without actual germination followed by drying, increases the germination, stand establishment and stress tolerance in different crops. Seed priming with living bacterial inoculum is termed as biopriming that involves the application of plant growth promoting rhizobacteria. It increases speed and uniformity of germination; also ensures rapid, uniform and high establishment of crops; and hence improves harvest quality and yield. Seed biopriming allows the bacteria to enter/adhere the seeds and also acclimatization of bacteria in the prevalent conditions. This review focuses on methods used for biopriming, and also the role in improving crop productivity and stress tolerance along with prospects of this technology. The comparison of methods being followed is also reviewed proposing biopriming as a promising technique for application of beneficial microbes to the seeds. PMID:27222220

  8. The Promoting Effect of Ishige sinicola on Hair Growth

    PubMed Central

    Kang, Jung-Il; Kim, Eun-JI; Kim, Min-Kyoung; Jeon, You-Jin; Kang, Sung-Myung; Koh, Young-Sang; Yoo, Eun-Sook; Kang, Hee-Kyoung

    2013-01-01

    This study was conducted to evaluate the promoting effect of Ishige sinicola, an alga native to Jeju Island, Korea, on hair growth. When vibrissa follicles were cultured in the presence of I. sinicola extract for 21 days, I. sinicola extract increased hair-fiber length. After topical application of I. sinicola extract onto the back of C57BL/6 mice, anagen progression of the hair shaft was induced. The I. sinicola extract significantly inhibited the activity of 5α-reductase. Treatment of immortalized vibrissa dermal papilla cells (DPCs) with I. sinicola extract resulted in increase of cell proliferation, which was accompanied by the increase of phospho-GSK3β level, β-catenin, Cyclin E and CDK2, whereas p27kip1 was down-regulated. In particular, octaphlorethol A, an isolated component from the I. sinicola extract, inhibited the activity of 5α-reductase and increased the proliferation of DPCs. These results suggest that I. sinicola extract and octaphlorethol A, a principal of I. sinicola, have the potential to treat alopecia via the proliferation of DPCs followed by the activation of β-catenin pathway, and the 5α-reductase inhibition. PMID:23708185

  9. ACSL4 promotes prostate cancer growth, invasion and hormonal resistance.

    PubMed

    Wu, Xinyu; Deng, Fangming; Li, Yirong; Daniels, Garrett; Du, Xinxin; Ren, Qinghu; Wang, Jinhua; Wang, Ling Hang; Yang, Yang; Zhang, Valerio; Zhang, David; Ye, Fei; Melamed, Jonathan; Monaco, Marie E; Lee, Peng

    2015-12-29

    Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and β-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC. PMID:26636648

  10. Resistance to targeted cancer drugs through hepatocyte growth factor signaling

    PubMed Central

    Heynen, Guus JJE; Fonfara, Aldona; Bernards, René

    2014-01-01

    Cancer therapeutics that target a signaling pathway to which the cancer cells are addicted can deliver dramatic initial responses, but resistance is nearly always inevitable. A variety of mechanisms that cancer cells employ to escape from targeted cancer drugs have been described. We review here the role of Hepatocyte Growth Factor (HGF) and its receptor MET in drug resistance. We present data demonstrating that HGF can confer resistance to a number of kinase inhibitors in a variety of cancer cell lines and discuss our results in relation to the findings of others. Together, these data point at a major role for HGF/MET signaling in resistance to a variety of targeted cancer drugs. PMID:25426675

  11. APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.

    PubMed

    García-Castro, Araceli; Zonca, Manuela; Florindo-Pinheiro, Douglas; Carvalho-Pinto, Carla E; Cordero, Alex; Gutiérrez del Fernando, Burgo; García-Grande, Aránzazu; Mañes, Santos; Hahne, Michael; González-Suárez, Eva; Planelles, Lourdes

    2015-05-01

    APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL. The inflammatory stimulus poly I:C, a toll-like receptor (TLR) 3 ligand, enhanced APRIL secretion. Silencing experiments decreased cell proliferation, demonstrating that APRIL is a critical autocrine factor for breast tumor growth. Studies of 4T1 orthotopic breast tumors in APRIL transgenic mice showed that an APRIL-enriched environment increased tumor growth and promoted lung metastasis associated with enhanced tumor cell proliferation; BCMA and TACI expression suggests that both participate in these processes. We detected APRIL, BCMA and TACI in human luminal, triple-negative breast carcinomas and HER2 breast carcinomas, with increased levels in more aggressive basal tumors. APRIL was observed near Ki67(+) nuclei and was distributed heterogeneously in the cancer cells, in the leukocyte infiltrate, and in the myoepithelial layer adjacent to the tumor area; these results imply that APRIL provides proliferation signals to tumor cells through paracrine and autocrine signaling. Our study identifies participation of APRIL signaling in breast cancer promotion; we propose impairment of this pathway as a potential therapeutic strategy. PMID:25750171

  12. miR-17-92 Cluster Promotes Cholangiocarcinoma Growth

    PubMed Central

    Zhu, Hanqing; Han, Chang; Lu, Dongdong; Wu, Tong

    2015-01-01

    miR-17-92 is an oncogenic miRNA cluster implicated in the development of several cancers; however, it remains unknown whether the miR-17-92 cluster is able to regulate cholangiocarcinogenesis. This study was designed to investigate the biological functions and molecular mechanisms of the miR-17-92 cluster in cholangiocarcinoma. In situ hybridization and quantitative RT-PCR analysis showed that the miR-17-92 cluster is highly expressed in human cholangiocarcinoma cells compared with the nonneoplastic biliary epithelial cells. Forced overexpression of the miR-17-92 cluster or its members, miR-92a and miR-19a, in cultured human cholangiocarcinoma cells enhanced tumor cell proliferation, colony formation, and invasiveness, in vitro. Overexpression of the miR-17-92 cluster or miR-92a also enhanced cholangiocarcinoma growth in vivo in hairless outbred mice with severe combined immunodeficiency (SHO-PrkdcscidHrhr). The tumor-suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), was identified as a bona fide target of both miR-92a and miR-19a in cholangiocarcinoma cells via sequence prediction, 3′ untranslated region luciferase activity assay, and Western blot analysis. Accordingly, overexpression of the PTEN open reading frame protein (devoid of 3′ untranslated region) prevented miR-92a– or miR-19a–induced cholangiocarcinoma cell growth. Microarray analysis revealed additional targets of the miR-17-92 cluster in human cholangiocarcinoma cells, including APAF-1 and PRDM2. Moreover, we observed that the expression of the miR-17-92 cluster is regulated by IL-6/Stat3, a key oncogenic signaling pathway pivotal in cholangiocarcinogenesis. Taken together, our findings disclose a novel IL-6/Stat3–miR-17-92 cluster–PTEN signaling axis that is crucial for cholangiocarcinogenesis and tumor progression. PMID:25239565

  13. Signaling effectors underlying pathologic growth and remodeling of the heart

    PubMed Central

    van Berlo, Jop H.; Maillet, Marjorie; Molkentin, Jeffery D.

    2013-01-01

    Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials. PMID:23281408

  14. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma

    PubMed Central

    Furnari, Frank B.; Cloughesy, Timothy F.; Cavenee, Webster K.; Mischel, Paul S.

    2016-01-01

    As tumours evolve, the daughter cells of the initiating cell often become molecularly heterogeneous and develop different functional properties and therapeutic vulnerabilities. In glioblastoma (GBM), a lethal form of brain cancer, the heterogeneous expression of the epidermal growth factor receptor (EGFR) poses a substantial challenge for the effective use of EGFR-targeted therapies. Understanding the mechanisms that cause EGFR heterogeneity in GBM should provide better insights into how they, and possibly other amplified receptor tyrosine kinases, affect cellular signalling, metabolism and drug resistance. PMID:25855404

  15. Intracellular signals involved in the effects of insulin-like growth factors and neuregulins on myofibre formation.

    PubMed

    Zorzano, Antonio; Kaliman, Perla; Gumà, Anna; Palacín, Manuel

    2003-02-01

    A number of extracellular factors are involved in the embryonic development of skeletal muscle and the muscle regeneration that is triggered in response to muscle damage. Some of them, such as insulin-like growth factors (IGFs), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), transforming growth factor (TGF)-like molecules, leukemia inhibitor factor (LIF) or platelet-derived growth factors (PDGFs), are involved in the activation of cell proliferation that operates before muscle differentiation. In addition, factors such as IGFs, neuregulins (NRGs), sonic hedgehog (Shh) or Wnt promote muscle differentiation. Here, we review the intracellular signals that are triggered in the myogenic effect of IGFs and neuregulin and we describe common pathways. A fuller understanding of the signalling pathways triggered by these factors may permit the design of new tools for muscle regeneration therapy. PMID:12464385

  16. Notch signaling promotes airway mucous metaplasia and inhibits alveolar development.

    PubMed

    Guseh, J Sawalla; Bores, Sam A; Stanger, Ben Z; Zhou, Qiao; Anderson, William J; Melton, Douglas A; Rajagopal, Jayaraj

    2009-05-01

    The airways are conduits that transport atmospheric oxygen to the distal alveolus. Normally, airway mucous cells are rare. However, diseases of the airway are often characterized by mucous metaplasia, in which there are dramatic increases in mucous cell numbers. As the Notch pathway is known to regulate cell fate in many contexts, we misexpressed the active intracellular domain of the mouse Notch1 receptor in lung epithelium. Notch misexpression resulted in an increase in mucous cells and a decrease in ciliated cells in the airway. Similarly, mouse embryonic tracheal explants and adult human airway epithelium treated with Notch agonists displayed increased mucous cell numbers and decreased ciliated cell numbers. Notch antagonists had the opposite effect. Notably, Notch antagonists blocked IL13-induced mucous metaplasia. IL13 has a well-established role as an inflammatory mediator of mucous metaplasia and functions through Stat6-mediated gene transcription. We found that Notch ligands, however, are able to cause mucous metaplasia in Stat6-null cultured trachea, thus identifying a novel pathway that stimulates mucous metaplasia. Notch signaling may therefore play an important role in airway disease and, by extension, Notch antagonists may have therapeutic value. Conversely, in the distal lung, Notch misexpression prevented the differentiation of alveolar cell types. Instead, the distal lung formed cysts composed of cells that were devoid of alveolar markers but that expressed some, but not all, markers of proximal airway epithelium. Occasional distal cystic cells appeared to differentiate into normal proximal airway cells, suggesting that ectopic Notch signaling arrests the normal differentiation of distal lung progenitors before they initiate an alveolar program. PMID:19369400

  17. Characterization of the bioactive metabolites from a plant growth-promoting rhizobacteria and their exploitation as antimicrobial and plant growth-promoting agents.

    PubMed

    George, Emrin; Kumar, S Nishanth; Jacob, Jubi; Bommasani, Bhaskara; Lankalapalli, Ravi S; Morang, P; Kumar, B S Dileep

    2015-05-01

    A plant growth-promoting bacterial strain, PM 105, isolated from a tea plantation soil from the North Eastern region of India was identified as Pseudomonas aeruginosa through classical and 16S ribosomal DNA (rDNA) gene sequencing. Further studies with this strain confirmed broad spectrum antifungal activity against ten human and plant pathogenic fungal pathogens viz. Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus tubingensis, Candida albicans, Colletotrichum gloeosporioides, Fusarium oxysporum, Pencillium expansum, Rhizoctonia solani, Trichophyton rubrum besides growth-promoting property in cowpea (Vigna unguiculata) and pigeon pea (Cajanus cajan). However, no antibacterial property was exhibited by this strain against the four test bacterial pathogens tested in agar overlay method. The crude bioactive metabolites produced by this strain were isolated with three different solvents that exhibited significant antimicrobial and plant growth-promoting activity. Chloroform extract recorded significant antimicrobial and plant growth-promoting activity. Three major compounds viz. 1-hydroxyphenazine, pyocyanin, and phenazine-1-carboxamide were purified and characterized from crude extracts of this strain by various spectral data. The purified compounds recorded prominent antimicrobial activity but failed to establish the plant growth promotion activity in test crop plants under gnotobiotic conditions. Pyocyanin recorded significant antimicrobial activity, and best activity was recorded against T. rubrum (29 mm), followed by P. expansum (28 mm). These results suggest the use of PM 105 as plant growth-promoting agent in crop plants after successful field trials. PMID:25832181

  18. Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

    PubMed Central

    Takayama, K; Reynolds, PN; Adachi, Y; Kaliberova, L; Uchino, J; Nakanishi, Y; Curiel, DT

    2007-01-01

    Treatment of advanced lung cancer is one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and has an extremely poor prognosis. Thus, new therapeutic approaches are needed. Lung tumor formation depends on angiogenesis in which the vascular endothelial growth factor (VEGF) produced by cancer cells plays a pivotal role. Neutralizing VEGF with a soluble VEGF receptor suppresses tumor growth; however, the anticancer effect with this therapy is weakened after the intratumoral vascular network is completed. In this study, we turned the expression of VEGF by tumors to therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the human VEGF promoter. This virus achieved good levels of viral replication in lung cancer cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with tropism modification of the virus to express the knob domain of Ad3, which improved infectivity for cancer cells. These VEGF promoter-based CRAds also showed a significant cell killing effect for various types of cancer lines other than lung cancer. Conversely, the VEGF promoter has low activity in normal tissues, and the CRAd caused no damage to normal bronchial epithelial cells. Since tumor-associated angiogenesis via VEGF signalling is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that VEGF promoter-based CRAds have the potential to be an effective strategy for cancer treatment. PMID:17024232

  19. Thymosin β4 Prevents Angiotensin II-Induced Cardiomyocyte Growth by Regulating Wnt/WISP Signaling.

    PubMed

    Li, Li; Guleria, Rakeshwar S; Thakur, Suresh; Zhang, Cheng-Lin; Pan, Jing; Baker, Kenneth M; Gupta, Sudhiranjan

    2016-08-01

    Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocyte hypertrophy is currently unknown. The purpose of this study was to determine the cardio-protective effect of Tβ4 in angiotensin II (Ang II)-induced cardiomyocyte growth. Neonatal rat ventricular cardiomyocytes (NRVM) were pretreated with Tβ4 followed by Ang II stimulation. Cell size, hypertrophy marker gene expression and Wnt signaling components, β-catenin, and Wnt-induced secreted protein-1 (WISP-1) were evaluated by quantitative real-time PCR, Western blotting and fluorescent microscopy. Pre-treatment of Tβ4 resulted in reduction of cell size, hypertrophy marker genes and Wnt-associated gene expression, and protein levels; induced by Ang II in cardiomyocyte. WISP-1 was overexpressed in NRVM and, the effect of Tβ4 in Ang II-induced cardiomyocyte growth was evaluated. WISP-1 overexpression promoted cardiomyocytes growth and was reversed by pretreatment with Tβ4. This is the first report which demonstrates that Tβ4 targets Wnt/WISP-1 to protect Ang II-induced cardiomyocyte growth. J. Cell. Physiol. 231: 1737-1744, 2016. © 2015 Wiley Periodicals, Inc. PMID:26627308

  20. Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.

    PubMed

    Bao, Ying-Na; Cao, Xue; Luo, Dong-Hua; Sun, Rui; Peng, Li-Xia; Wang, Lin; Yan, Yong-Pan; Zheng, Li-Sheng; Xie, Ping; Cao, Yun; Liang, Ying-Ying; Zheng, Fang-Jing; Huang, Bi-Jun; Xiang, Yan-Qun; Lv, Xing; Chen, Qiu-Yan; Chen, Ming-Yuan; Huang, Pei-Yu; Guo, Ling; Mai, Hai-Qiang; Guo, Xiang; Zeng, Yi-Xin; Qian, Chao-Nan

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China and Southeast Asia, with the highest metastasis rate among head and neck cancers. The mechanisms underlying NPC progression remain poorly understood. Genome-wide expression profiling on 18 NPC vs. 18 noncancerous nasopharyngeal tissues together with GeneGo pathway analysis and expression verification in NPC cells and tissues revealed a potential role of urokinase-type plasminogen activator receptor (uPAR) in NPC progression, which has not been investigated in NPC. We then observed that uPAR expression is increased in poorly differentiated, highly metastatic NPC cells compared with lowly metastatic cells or differentiated NPC cells. In vitro studies demonstrated that uPAR regulates NPC cell growth, colony formation, migration, and invasion and promotes the epithelial-mesenchymal transition (EMT). Additional tumor xenograft and spontaneous metastasis experiments revealed that uPAR promotes NPC cell growth and metastasis in vivo. The JAK-STAT pathway is involved in uPAR-regulated signaling in NPC cells as determined by immunoblotting. Moreover, uPAR-mediated growth and motility is partially abolished upon treatment with the Jak1/Jak2 inhibitor INCB018424. We suppressed uPA expression in uPAR-overexpressing NPC cells and found that uPAR-mediated cellular growth and motility is not exclusively dependent on uPA. In summary, uPAR is a significant regulator of NPC progression and could serve as a promising therapeutic target. PMID:24763226

  1. A Signaling Lipid Associated with Alzheimer's Disease Promotes Mitochondrial Dysfunction.

    PubMed

    Kennedy, Michael A; Moffat, Tia C; Gable, Kenneth; Ganesan, Suriakarthiga; Niewola-Staszkowska, Karolina; Johnston, Anne; Nislow, Corey; Giaever, Guri; Harris, Linda J; Loewith, Robbie; Zaremberg, Vanina; Harper, Mary-Ellen; Dunn, Teresa; Bennett, Steffany A L; Baetz, Kristin

    2016-01-01

    Fundamental changes in the composition and distribution of lipids within the brain are believed to contribute to the cognitive decline associated with Alzheimer's disease (AD). The mechanisms by which these changes in lipid composition affect cellular function and ultimately cognition are not well understood. Although "candidate gene" approaches can provide insight into the effects of dysregulated lipid metabolism they require a preexisting understanding of the molecular targets of individual lipid species. In this report we combine unbiased gene expression profiling with a genome-wide chemogenomic screen to identify the mitochondria as an important downstream target of PC(O-16:0/2:0), a neurotoxic lipid species elevated in AD. Further examination revealed that PC(O-16:0/2:0) similarly promotes a global increase in ceramide accumulation in human neurons which was associated with mitochondrial-derived reactive oxygen species (ROS) and toxicity. These findings suggest that PC(O-16:0/2:0)-dependent mitochondrial dysfunction may be an underlying contributing factor to the ROS production associated with AD. PMID:26757638

  2. Apelin/APJ signaling promotes hypoxia-induced proliferation of endothelial progenitor cells via phosphoinositide-3 kinase/Akt signaling.

    PubMed

    Zhang, Jingchang; Liu, Qiming; Hu, Xinqun; Fang, Zhenfei; Huang, Feng; Tang, Liang; Zhou, Shenghua

    2015-09-01

    Endothelial progenitor cells (EPCs) can adhere to the endothelium at sites of hypoxia/ischemia and participate in the formation of novel vessels through differentiating into endothelial cells (ECs). Apelin is an endogenous ligand for the G protein‑coupled receptor APJ, and apelin/APJ signaling has a role in cardiovascular function. The present study aimed to investigate the role of apelin/APJ signaling in the regulation of EPC proliferation under hypoxia. The results showed that hypoxia was able to induce EPC proliferation, accompanied with an upregulation of hypoxia‑inducible factor (HIF)‑1α as well as apelin/APJ signaling. Further investigation indicated that siRNA‑mediated knockdown of apelin or APJ expression attenuated the hypoxia‑induced proliferation of EPCs, suggesting that apelin/APJ signaling has an important role in hypoxia‑induced EPC proliferation. Moreover, the phosphoinositide‑3 kinase (PI3K)/Akt signaling pathway was found to be involved in the apelin/APJ‑mediated EPC proliferation under hypoxia. Based on these findings, the present study suggested that hypoxia‑induced upregulation of HIF‑1α promotes the expression of apelin and APJ, which further activate the downstream PI3K/Akt signaling pathway, a key promoter of EPC proliferation. In conclusion, the present study highlighted the role of apelin/APJ in the regulation of EPC proliferation, and apelin/APJ may therefore serve as a potential target for the prevention of hypoxic ischemic injury. PMID:26018184

  3. HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells.

    PubMed

    Chushi, Li; Wei, Wu; Kangkang, Xie; Yongzeng, Feng; Ning, Xie; Xiaolei, Chen

    2016-08-01

    Alteration of metabolic profile is one of the hallmarks of cancer cells. Statin, the inhibitors for synthesis of cholesterol, has shown anti-cancer effects on the gastric cancer cells. However, the functions of its target, HMGCR, in the progression of gastric cancer remain unknown. In the present study, we investigated the expression profile and the biological functions of HMGCR in gastric cancer. It was found that the expression of HMGCR was increased in gastric cancer tissues. Over-expression of HMGCR promoted the growth and migration of gastric cancer cells, while knocking down the expression of HMGCR inhibited the growth, migration and tumorigenesis of gastric cancer cells. In the further molecular mechanism study, HMGCR was shown to activate Hedgehog/Gli1 signaling and promoted the expression of Gli1 target genes. Taken together, this study demonstrated the tumor-promoting effects of HMGCR in gastric cancer and suggested HMGCR as a promising therapeutic target. PMID:27085483

  4. Floc Growth and Changes in ADV Acoustic Backscatter Signal

    NASA Astrophysics Data System (ADS)

    Rouhnia, M.; Keyvani, A.; Strom, K.

    2013-12-01

    A series of experiments were conducted to examine the effect of mud floc growth on the acoustic back-scatter signal recorded by a Nortek Vector acoustic Doppler velocimeter (ADV). Several studies have shown that calibration equations can be developed to link the backscatter strength with average suspended sediment concentration (SSC) when the sediment particle size distribution remains constant. However, when mud is present, the process of flocculation can alter the suspended particle size distribution. Past studies have shown that it is still unclear as to the degree of dependence of the calibration equation on changes in floc size. Part of the ambiguity lies in the fact that flocs can be porous and rather loosely packed and therefore might not scatter to the same extent as a grain of sand. In addition, direct, detailed measurements of floc size have not accompanied experiments examining the dependence of ADV backscatter and suspended sediment concentration. In this research, a set of laboratory experiments is used to test how floc growth affects the backscatter strength. The laboratory data is examined in light of an analytic model that was developed based on scatter theory to account for changes in both SSC and the floc properties of size and density. For the experiments, a turbulent suspension was created in a tank with a rotating paddle. Fixed concentrations of a mixture of kaolinite and montmorillonite were added to the tank in a step-wise manner. For each step, the flocs were allowed to grow to their equilibrium size before breaking the flocs with high turbulent mixing, adding more sediment, and then returning the mixing rate to a range suitable for the re-growth of flocs. During each floc growth phase, data was simultaneously collected at the same elevation in the tank using a floc camera to capture the changes in floc size, a Nortek Vector ADV for the acoustic backscatter, and a Campbell Scientific OBS 3+ for optical backscatter. Physical samples of the

  5. Interferon-α signaling promotes embryonic HSC maturation.

    PubMed

    Kim, Peter Geon; Canver, Matthew C; Rhee, Catherine; Ross, Samantha J; Harriss, June V; Tu, Ho-Chou; Orkin, Stuart H; Tucker, Haley O; Daley, George Q

    2016-07-14

    In the developing mouse embryo, the first hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros (AGM) and mature as they transit through the fetal liver (FL). Compared with FL and adult HSCs, AGM HSCs have reduced repopulation potential in irradiated adult transplant recipients but mechanisms underlying this deficiency in AGM HSCs are poorly understood. By co-expression gene network analysis, we deduced that AGM HSCs show lower levels of interferon-α (IFN-α)/Jak-Stat1-associated gene expression than FL HSCs. Treatment of AGM HSCs with IFN-α enhanced long-term hematopoietic engraftment and donor chimerism. Conversely, IFN-α receptor-deficient AGMs (Ifnαr1(-/-)), had significantly reduced donor chimerism. We identify adenine-thymine-rich interactive domain-3a (Arid3a), a factor essential for FL and B lymphopoiesis, as a key transcriptional co-regulator of IFN-α/Stat1 signaling. Arid3a occupies the genomic loci of Stat1 as well as several IFN-α effector genes, acting to regulate their expression. Accordingly, Arid3a(-/-) AGM HSCs had significantly reduced transplant potential, which was rescued by IFN-α treatment. Our results implicate the inflammatory IFN-α/Jak-Stat pathway in the developmental maturation of embryonic HSCs, whose manipulation may lead to increased potency of reprogrammed HSCs for transplantation. PMID:27095787

  6. Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

    PubMed Central

    Obrador, Elena; Benlloch, María; Pellicer, José A.; Asensi, Miguel; Estrela, José M.

    2011-01-01

    B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show high metastatic activity in vivo. An intertissue flow of GSH, where the liver is the main reservoir, can increase GSH content in metastatic cells and promote their growth. We have studied here possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1- and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin in B16-F10-bearing mice) may facilitate GSH release from hepatocytes and its interorgan transport to metastatic growing foci. PMID:21393247

  7. BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways

    PubMed Central

    de Jesus Perez, Vinicio A.; Ali, Ziad; Alastalo, Tero-Pekka; Ikeno, Fumiaki; Sawada, Hirofumi; Lai, Ying-Ju; Kleisli, Thomas; Spiekerkoetter, Edda; Qu, Xiumei; Rubinos, Laura H.; Ashley, Euan; Amieva, Manuel; Dedhar, Shoukat

    2011-01-01

    We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)–β-catenin (βC) and Wnt–planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt–dependent manner, induces βC transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via α4-integrins. ILK-1 then induces the Wnt–PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1–mediated motility. Transfection of a Dvl mutant that binds βC without activating RhoA-Rac1 not only prevents BMP-2–mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent βC activity. Interfering with the Dvl-dependent Wnt–PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2–mediated tandem activation of Wnt–βC and Wnt–PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations. PMID:21220513

  8. Tumor growth and its effect on Magnetic Resonance Imaging signal

    NASA Astrophysics Data System (ADS)

    Cersosimo, Homero; Colon, Jorge; Ramos, Elio; Zypman, Fredy

    2000-03-01

    The goal of this project is twofold. On one hand, we have developed computer code based on simple probabilistic rules to model the growth (or shrinking) of cancerigenous tissue. We assume that initially there exists a differentiated cell, which has a time- dependent probability of reproducing. If it did reproduce, then we assume that it has a finite probability of dying before reproducing again. This simple model falls into the Eden-type kind, and presents appropriate bulk growth characteristics, as it follows Gompert observational law. We propose new methods of geometrical characterization of the tumor. Besides its total mass, we also consider higher multipolar order of mass distribution and surface fractal dimension. In addition, we study how the geometrical properties of the tumor affect the Magnetic Resonance Imaging (MRI) signal. To this end, we consider a human brain in the presence of radiofrequency fields. We calculate the MRI image of this object. Then, we introduce a tumor in the white-gray matter region and reobtain the MRI image. We associate the signal changes with the geometrical properties of the tumor.

  9. Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions

    PubMed Central

    Yamakawa, Hiroyuki; Muraoka, Naoto; Miyamoto, Kazutaka; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Umei, Tomohiko; Akiyama, Mizuha; Kuishi, Yuki; Kurokawa, Junko; Furukawa, Tetsushi; Fukuda, Keiichi; Ieda, Masaki

    2015-01-01

    Summary Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. PMID:26626177

  10. Effect of Trichoderma on plant growth: A balance between inhibition and growth promotion.

    PubMed

    Ousley, M A; Lynch, J M; Whipps, J M

    1993-11-01

    The effect of lettuce (Latuca sativa L.) germination and growth in nonsterilized potting compost of 0.1% and 1.0% w/w incorporation of fermenter biomass inocula of six strains of Trichoderma was investigated. Except for strains WT and T35 at 0.1 % w/w, all inocula inhibited germination. Biomass of strains WT, T35, 20, and 47 at 1.0% promoted shoot fresh weight, whereas strains TH1 and 8MF2 were inhibitory. In contrast, when biomass of strains WT, TH1, and 8MF2 was autoclaved and incorporated at 1%, shoot fresh weight was promoted, but the biomass of T35 was inhibitory. None of the strains incorporated at 0.1 % w/w increased shoot fresh weight, and autoclaved biomass of TH1, T35, and 20 incorporated at 0.1% w/w resulted in lower shoot fresh weights in comparison with uninoculated controls. The shoot dry weight of lettuce seedlings could be enhanced by germinating seeds in uninoculated compost and after five days' growth transferring them into WT-inoculated compost. Inoculum of strain TH1 when applied using this method was very inhibitory. With WT the degree of increase in shoot fresh weight and germination rate declined as the fermentation time to produce inocula was increased. PMID:24190096

  11. Cdo suppresses canonical Wnt signalling via interaction with Lrp6 thereby promoting neuronal differentiation

    PubMed Central

    Jeong, Myong-Ho; Ho, Seok-Man; Vuong, Tuan Anh; Jo, Shin-Bum; Liu, Guizhong; Aaronson, Stuart A.; Leem, Young-Eun; Kang, Jong-Sun

    2015-01-01

    Canonical Wnt signalling regulates expansion of neural progenitors and functions as a dorsalizing signal in the developing forebrain. In contrast, the multifunctional co-receptor Cdo promotes neuronal differentiation and is important for the function of the ventralizing signal, Shh. Here we show that Cdo negatively regulates Wnt signalling during neurogenesis. Wnt signalling is enhanced in Cdo-deficient cells, leading to impaired neuronal differentiation. The ectodomains of Cdo and Lrp6 interact via the Ig2 repeat of Cdo and the LDLR repeats of Lrp6, and the Cdo Ig2 repeat is necessary for Cdo-dependent Wnt inhibition. Furthermore, the Cdo-deficient dorsal forebrain displays stronger Wnt signalling activity, increased cell proliferation and enhanced expression of the dorsal markers and Wnt targets, Pax6, Gli3, Axin2. Therefore, in addition to promoting ventral central nervous system cell fates with Shh, Cdo promotes neuronal differentiation by suppression of Wnt signalling and provides a direct link between two major dorsoventral morphogenetic signalling pathways. PMID:25406935

  12. Leukemia inhibitory factor promotes tumor growth and metastasis in human osteosarcoma via activating STAT3.

    PubMed

    Liu, Bin; Lu, Yi; Li, Jinzhi; Liu, Yanping; Liu, Jian; Wang, Weiguo

    2015-10-01

    The leukemia inhibitory factor (LIF) has been demonstrated to be an oncogene and participated in multiple procedures during the initiation and progression of many human malignancies. However, the role of LIF in osteosarcoma is still largely unknown. Here, we performed a series of in vitro and in vivo experiments to investigate the expression and biological functions of LIF in osteosarcoma. Compared to that in the non-cancerous tissues, LIF was significantly overexpressed in a panel of 68 osteosarcoma samples (p < 0.0001). Moreover, the overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size, and shorter overall survival. In addition, knockdown of LIF notably suppressed the proliferation and invasion of osteosarcoma via blocking the STAT3 signal pathway; in contrast, treatment with the recombinant LIF protein significantly promoted the growth and invasion of osteosarcoma through enhancing the phosphorylation of STAT3, which can be partially neutralized by the STAT3 inhibitor, HO-3867. In conclusion, we demonstrated that LIF was frequently overexpressed in osteosarcoma, which could promote the growth and invasion through activating the STAT3 pathway. Our findings proposed that LIF might be a potent therapeutic target for osteosarcoma. PMID:26271643

  13. S-nitrosylation triggers ABI5 degradation to promote seed germination and seedling growth

    PubMed Central

    Albertos, Pablo; Romero-Puertas, María C.; Tatematsu, Kiyoshi; Mateos, Isabel; Sánchez-Vicente, Inmaculada; Nambara, Eiji; Lorenzo, Oscar

    2015-01-01

    Plant survival depends on seed germination and progression through post-germinative developmental checkpoints. These processes are controlled by the stress phytohormone abscisic acid (ABA). ABA regulates the basic leucine zipper transcriptional factor ABI5, a central hub of growth repression, while the reactive nitrogen molecule nitric oxide (NO) counteracts ABA during seed germination. However, the molecular mechanisms by which seeds sense more favourable conditions and start germinating have remained elusive. Here we show that ABI5 promotes growth via NO, and that ABI5 accumulation is altered in genetic backgrounds with impaired NO homeostasis. S-nitrosylation of ABI5 at cysteine-153 facilitates its degradation through CULLIN4-based and KEEP ON GOING E3 ligases, and promotes seed germination. Conversely, mutation of ABI5 at cysteine-153 deregulates protein stability and inhibition of seed germination by NO depletion. These findings suggest an inverse molecular link between NO and ABA hormone signalling through distinct posttranslational modifications of ABI5 during early seedling development. PMID:26493030

  14. CD166-mediated epidermal growth factor receptor phosphorylation promotes the growth of oral squamous cell carcinoma.

    PubMed

    Jia, Guodong; Wang, Xu; Yan, Ming; Chen, Wantao; Zhang, Ping

    2016-08-01

    CD166 has been considered a relatively specific marker of stem cells and cancer stem cells, and the altered expression of CD166 has also been reported as a prognostic marker of several other types of cancer. However, the molecular functions of CD166 in these cancer cells are largely unknown. In this study, we found that CD166 significantly enhanced epidermal growth factor receptor (EGFR) phosphorylation and prolonged epidermal growth factor (EGF)/EGFR signalling activation. In addition, EGF stimulation in CD166-overexpressing oral squamous carcinoma cells led to enhanced colony formation, invasion capacity and cytoskeletal re-organization in vitro and elevated tumourigenesis in vivo. Taken together, the results of our study identify CD166 as an intriguing therapeutic target for patients suffering from oral squamous cell carcinoma (OSCC). PMID:27424177

  15. A Recently Evolved Isoform of the Transcription Factor BES1 Promotes Brassinosteroid Signaling and Development in Arabidopsis thaliana

    PubMed Central

    Zhang, Chi; Wang, Xuelu

    2015-01-01

    Brassinosteroids (BRs) are essential steroid hormones that regulate plant growth and development. The transcription factor BRI1-EMS-SUPPRESSOR1 (BES1) regulates the expression of thousands of target genes in response to BRs. Here, we report an Arabidopsis thaliana-specific long isoform of BES1, BES1-L, which has stronger activity in promoting BR signaling than the canonical and widely used short BES1-S. The BES1-L isoform contains an additional N-terminal bipartite nuclear localization signal, which strongly promotes its nuclear localization. BES1-L also promotes the nuclear localization of BES1-S and BRASSINAZOLE-RESISTANT1 via dimerization. The transcription of BES1-L and BES1-S is differentially regulated by BRs due to the presence of G-box element in the BES1-S promoter. Moreover, BES1-L uniquely exists in the majority of A. thaliana ecotypes, but not in other species, even its Brassicaceae relatives, including Arabidopsis lyrata. The phenotypes of the BES1-L overexpression lines and plants with truncated BES1-L indicate that BES1-L is a more important isoform of BES1 in Arabidopsis and may have contributed to the evolution and expansion of A. thaliana. PMID:25649439

  16. Genome Sequence of Enterobacter radicincitans DSM16656T, a Plant Growth-Promoting Endophyte

    PubMed Central

    Witzel, Katja; Gwinn-Giglio, Michelle; Nadendla, Suvarna; Shefchek, Kent

    2012-01-01

    Enterobacter radicincitans sp. nov. DSM16656T represents a new species of the genus Enterobacter which is a biological nitrogen-fixing endophytic bacterium with growth-promoting effects on a variety of crop and model plant species. The presence of genes for nitrogen fixation, phosphorous mobilization, and phytohormone production reflects this microbe's potential plant growth-promoting activity. PMID:22965092

  17. Using Community Health Workers in Community-Based Growth Promotion: What Stakeholders Think

    ERIC Educational Resources Information Center

    Afulani, Patience A.; Awoonor-Williams, John K.; Opoku, Ernest C.; Asunka, Joseph

    2012-01-01

    The Nutrition and Malaria Control for Child Survival Project is a community-based growth promotion project that utilizes Community Health Workers (CHWs), referred to as Community Child Growth Promoters (CCGPs), as the principal change agents. The purpose of this study was to identify perceptions of key stakeholders about the project and the role…

  18. Genome Sequence of Bacillus mycoides B38V, a Growth-Promoting Bacterium of Sunflower.

    PubMed

    Ambrosini, Adriana; Sant'Anna, Fernando Hayashi; de Souza, Rocheli; Tadra-Sfeir, Michele; Faoro, Helisson; Alvarenga, Samuel M; Pedrosa, Fabio Oliveira; Souza, Emanuel Maltempi; Passaglia, Luciane M P

    2015-01-01

    Bacillus mycoides B38V is a bacterium isolated from the sunflower rhizosphere that is able to promote plant growth and N uptake. The genome of the isolate has approximately 5.80 Mb and presents sequence codifiers for plant growth-promoting characteristics, such as nitrate reduction and ammonification and iron-siderophore uptake. PMID:25838494

  19. Genome Sequence of Bacillus mycoides B38V, a Growth-Promoting Bacterium of Sunflower

    PubMed Central

    Ambrosini, Adriana; Sant’Anna, Fernando Hayashi; de Souza, Rocheli; Tadra-Sfeir, Michele; Faoro, Helisson; Alvarenga, Samuel M.; Pedrosa, Fabio Oliveira; Souza, Emanuel Maltempi

    2015-01-01

    Bacillus mycoides B38V is a bacterium isolated from the sunflower rhizosphere that is able to promote plant growth and N uptake. The genome of the isolate has approximately 5.80 Mb and presents sequence codifiers for plant growth-promoting characteristics, such as nitrate reduction and ammonification and iron-siderophore uptake. PMID:25838494

  20. Bacillus spp. from rainforest soil promote plant growth under limited nitrogen conditions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aims: The aim of this study was to evaluate effects of PGPR (Plant Growth Promoting Rhizobacteria) isolated from rainforest on different plants under limited nitrogen conditions. Methods and Results: Bacterial isolates from a Peruvian rainforest soil were screened for plant growth promoting effects...

  1. Cell responses to FGFR3 signalling: growth, differentiation and apoptosis

    SciTech Connect

    L'Hote, Corine G.M. . E-mail: Corine.LHote@cancer.org.uk; Knowles, Margaret A.

    2005-04-01

    FGFR3 is a receptor tyrosine kinase (RTK) of the FGF receptor family, known to have a negative regulatory effect on long bone growth. Fgfr3 knockout mice display longer bones and, accordingly, most germline-activating mutations in man are associated with dwarfism. Somatically, some of the same activating mutations are associated with the human cancers multiple myeloma, cervical carcinoma and carcinoma of the bladder. How signalling through FGFR3 can lead to either chondrocyte apoptosis or cancer cell proliferation is not fully understood. Although FGFR3 can be expressed as two main splice isoforms (IIIb or IIIc), there is no apparent link with specific cell responses, which may rather be associated with the cell type or its differentiation status. Depending on cell type, differential activation of STAT proteins has been observed. STAT1 phosphorylation seems to be involved in inhibition of chondrocyte proliferation while activation of the ERK pathway inhibits chondrocyte differentiation and B-cell proliferation (as in multiple myeloma). The role of FGFR3 in epithelial cancers (bladder and cervix) is not known. Some of the cell specificity may arise via modulation of signalling by crosstalk with other signalling pathways. Recently, inhibition of the ERK pathway in achondroplastic mice has provided hope for an approach to the treatment of dwarfism. Further understanding of the ability of FGFR3 to trigger different responses depending on cell type and cellular context may lead to treatments for both skeletal dysplasias and cancer.

  2. ZmGRF, a GA regulatory factor from maize, promotes flowering and plant growth in Arabidopsis.

    PubMed

    Xu, Miaoyun; Lu, Yunming; Yang, Hongmei; He, Jingcheng; Hu, Zhiqiu; Hu, Xiaolong; Luan, Mingda; Zhang, Lan; Fan, Yunliu; Wang, Lei

    2015-01-01

    Transcription factors that act as positive regulators of gibberellin (GA) biosynthetic genes in plants are not well understood. A nuclear-localized basic leucine zipper transcription factor, ZmGRF, was isolated from maize. The core DNA sequence motif recognized for binding by ZmGRF was CCANNTGGC. ZmGRF overexpression in transgenic Arabidopsis plants promoted flowering, stem elongation, and cell expansion. Chromatin immunoprecipitation assays revealed that ZmGRF bound directly to the cis-element CCANNTGGC in the promoter of the Arabidopsis ent-kaurene oxidase (AtKO1) gene and promoted AtKO1 expression. GA4 content increased by 372-567% in transgenic Arabidopsis plants overexpressing ZmGRF compared to wild-type control plants. The GIBBERELLIN-INSENSITIVE DWARF1 gene, which encodes a GA receptor, was also upregulated and the growth-repressing DELLA protein gene GA INSENSITIVE was downregulated. Our results showed ZmGRF functioned through the GA-signaling pathway. PMID:25477078

  3. Fibroblast growth factor 8 increases breast cancer cell growth by promoting cell cycle progression and by protecting against cell death

    SciTech Connect

    Nilsson, Emeli M.; Brokken, Leon J.S.; Haerkoenen, Pirkko L.

    2010-03-10

    Fibroblast growth factor 8 (FGF-8) is expressed in a large proportion of breast cancers, whereas its level in normal mammary gland epithelium is low. Previous studies have shown that FGF-8b stimulates breast cancer cell growth in vitro and in vivo. To explore the mechanisms by which FGF-8b promotes growth, we studied its effects on cell cycle regulatory proteins and signalling pathways in mouse S115 and human MCF-7 breast cancer cells. We also studied the effect of FGF-8b on cell survival. FGF-8b induced cell cycle progression and up-regulated particularly cyclin D1 mRNA and protein in S115 cells. Silencing cyclin D1 with siRNA inhibited most but not all FGF-8b-induced proliferation. Inhibition of the FGF-8b-activated ERK/MAPK pathway decreased FGF-8b-stimulated proliferation. Blocking the constitutively active PI3K/Akt and p38 MAPK pathways also lowered FGF-8b-induced cyclin D1 expression and proliferation. Corresponding results were obtained in MCF-7 cells. In S115 and MCF-7 mouse tumours, FGF-8b increased cyclin D1 and Ki67 levels. Moreover, FGF-8b opposed staurosporine-induced S115 cell death which effect was blocked by inhibiting the PI3K/Akt pathway but not the ERK/MAPK pathway. In conclusion, our results suggest that FGF-8b increases breast cancer cell growth both by stimulating cell cycle progression and by protecting against cell death.

  4. VEGF Silencing Inhibits Human Osteosarcoma Angiogenesis and Promotes Cell Apoptosis via PI3K/AKT Signaling Pathway.

    PubMed

    Zhao, Jian; Zhang, Zi-Ru; Zhao, Na; Ma, Bao-An; Fan, Qing-Yu

    2015-11-01

    Vascular endothelial growth factor (VEGF) is one of the most effective angiogenic factors that promote generation of tumor vasculature. VEGF is usually up-regulated in multiple cancers including osteosarcoma and glioma. To further explore the potential molecular mechanism that inhibits tumor growth induced by interference of VEGF expression, we constructed a Lv-shVEGF vector and assessed the efficiency of VEGF silencing and its influence in U2OS cells. The data demonstrate that Lv-shVEGF has high inhibition efficiency on VEGF expression, which inhibits proliferation and promotes apoptosis of U2OS cells in vitro. Our results also indicate that inhibition of VEGF expression suppresses osteosarcoma tumor growth in vivo and reduces osteosarcoma angiogenesis. We also found that the activations of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) were considerably reduced after osteosarcoma cells were treated with Lv-shVEGF. Taken together, our data demonstrate that VEGF silencing suppresses cell proliferation, promotes cell apoptosis, and reduces osteosarcoma angiogenesis through inactivation of PI3K/AKT signaling pathway. PMID:27352347

  5. Promotion of growth by Coenzyme Q10 is linked to gene expression in C. elegans.

    PubMed

    Fischer, Alexandra; Niklowitz, Petra; Menke, Thomas; Döring, Frank

    2014-10-01

    Coenzyme Q (CoQ, ubiquinone) is an essential component of the respiratory chain, a cofactor of pyrimidine biosynthesis and acts as an antioxidant in extra mitochondrial membranes. More recently CoQ has been identified as a modulator of apoptosis, inflammation and gene expression. CoQ deficient Caenorhabditis elegans clk-1 mutants show several phenotypes including a delayed postembryonic growth. Using wild type and two clk-1 mutants, here we established an experimental set-up to study the consequences of endogenous CoQ deficiency or exogenous CoQ supply on gene expression and growth. We found that a deficiency of endogenous CoQ synthesis down-regulates a cluster of genes that are important for growth (i.e., RNA polymerase II, eukaryotic initiation factor) and up-regulates oxidation reactions (i.e., cytochrome P450, superoxide dismutase) and protein interactions (i.e., F-Box proteins). Exogenous CoQ supply partially restores the expression of these genes as well as the growth retardation of CoQ deficient clk-1 mutants. On the other hand exogenous CoQ supply does not alter the expression of a further sub-set of genes. These genes are involved in metabolism (i.e., succinate dehydrogenase complex), cell signalling or synthesis of lectins. Thus, our work provides a comprehensive overview of genes which can be modulated in their expression by endogenous or exogenous CoQ. As growth retardation in CoQ deficiency is linked to the gene expression profile we suggest that CoQ promotes growth via gene expression. PMID:25234594

  6. Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

    PubMed Central

    Shah, Nisarg J.; Hyder, Md. Nasim; Quadir, Mohiuddin A.; Dorval Courchesne, Noémie-Manuelle; Seeherman, Howard J.; Nevins, Myron; Spector, Myron; Hammond, Paula T.

    2014-01-01

    Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration. PMID:25136093

  7. hARIP2 is a putative growth-promoting factor involved in human colon tumorigenesis.

    PubMed

    Gao, Rui-Feng; Li, Zhan-Dong; Jiang, Jing; Yang, Li-Hua; Zhu, Ke-Tong; Lin, Rui-Xin; Li, Hao; Zhao, Quan; Zhang, Nai-Sheng

    2014-01-01

    Activin is a multifunctional growth and differentiation factor of the growth factor-beta (TGF-β) superfamily, which inhibits the proliferation of colon cancer cells. It induces phosphorylation of intracellular signaling molecules (Smads) by interacting with its type I and type II receptors. Previous studies showed that human activin receptor-interacting protein 2 (hARIP2) can reduce activin signaling by interacting with activin type II receptors; however, the activity of hARIP2 in colon cancer has yet to be detailed. In vitro, overexpression of hARIP2 reduced activin-induced transcriptional activity and enhanced cell proliferation and colony formation in human colon cancer HCT8 cells and SW620 cells. Also, hARIP2 promoted colon cancer cell apoptosis, suggesting that a vital role in the initial stage of colon carcinogenesis. In vivo, immunohistochemistry revealed that hARIP2 was expressed more frequently and much more intensely in malignant colon tissues than in controls. These results indicate that hARIP2 is involved in human colon tumorigenesis and could be a predictive maker for colon carcinoma aggressiveness. PMID:25374171

  8. Nordihydroguaiaretic Acid Inhibits Insulin-Like Growth Factor Signaling, Growth, and Survival in Human Neuroblastoma Cells

    PubMed Central

    Meyer, Gary E.; Chesler, Louis; Liu, Dandan; Gable, Karissa; Maddux, Betty A.; Goldenberg, David D.; Youngren, Jack F.; Goldfine, Ira D.; Weiss, William A.; Matthay, Katherine K.; Rosenthal, Stephen M.

    2010-01-01

    Neuroblastoma is a common pediatric malignancy that metastasizes to the liver, bone, and other organs. Children with metastatic disease have a less than 50% chance of survival with current treatments. Insulin-like growth factors (IGFs) stimulate neuroblastoma growth, survival, and motility, and are expressed by neuroblastoma cells and the tissues they invade. Thus, therapies that disrupt the effects of IGFs on neuroblastoma tumorigenesis may slow disease progression. We show that NVP-AEW541, a specific inhibitor of the IGF-I receptor (IGF-IR), potently inhibits neuroblastoma growth in vitro. Nordihydroguaiaretic acid (NDGA), a phenolic compound isolated from the creosote bush (Larrea divaricata), has anti-tumor properties against a number of malignancies, has been shown to inhibit the phosphorylation and activation of the IGF-IR in breast cancer cells, and is currently in Phase I trials for prostate cancer. In the present study in neuroblastoma, NDGA inhibits IGF-I-mediated activation of the IGF-IR and disrupts activation of ERK and Akt signaling pathways induced by IGF-I. NDGA inhibits growth of neuroblastoma cells and induces apoptosis at higher doses, causing IGF-I-resistant activation of caspase-3 and a large increase in the fraction of sub-G0 cells. In addition, NDGA inhibits the growth of xenografted human neuroblastoma tumors in nude mice. These results indicate that NDGA may be useful in the treatment of neuroblastoma and may function in part via disruption of IGF-IR signaling. PMID:17486636

  9. Transforming Growth Factor β/activin signalling induces epithelial cell flattening during Drosophila oogenesis

    PubMed Central

    Brigaud, Isabelle; Duteyrat, Jean-Luc; Chlasta, Julien; Le Bail, Sandrine; Couderc, Jean-Louis; Grammont, Muriel

    2015-01-01

    ABSTRACT Although the regulation of epithelial morphogenesis is essential for the formation of tissues and organs in multicellular organisms, little is known about how signalling pathways control cell shape changes in space and time. In the Drosophila ovarian epithelium, the transition from a cuboidal to a squamous shape is accompanied by a wave of cell flattening and by the ordered remodelling of E-cadherin-based adherens junctions. We show that activation of the TGFβ pathway is crucial to determine the timing, the degree and the dynamic of cell flattening. Within these cells, TGFβ signalling controls cell-autonomously the formation of Actin filament and the localisation of activated Myosin II, indicating that internal forces are generated and used to remodel AJ and to promote cytoskeleton rearrangement. Our results also reveal that TGFβ signalling controls Notch activity and that its functions are partly executed through Notch. Thus, we demonstrate that the cells that undergo the cuboidal-to-squamous transition produce active cell-shaping mechanisms, rather than passively flattening in response to a global force generated by the growth of the underlying cells. Thus, our work on TGFβ signalling provides new insights into the mechanisms through which signal transduction cascades orchestrate cell shape changes to generate proper organ structure. PMID:25681395

  10. Fibroblast growth factor (Fgf) signaling pathway regulates liver homeostasis in zebrafish.

    PubMed

    Tsai, Su-Mei; Liu, Da-Wei; Wang, Wen-Pin

    2013-04-01

    In mammals, fibroblast growth factor (FGF) signaling controls liver specification and regulates the metabolism of lipids, cholesterol, and bile acids. FGF signaling also promotes hepatocyte proliferation, and helps detoxify hepatotoxin during liver regeneration after partial hepatectomy. However, the function of Fgf in zebrafish liver is not yet well understood, specifically for postnatal homeostasis. The current study analyzed the expression of fgf receptors (fgfrs) in the liver of zebrafish. We then investigated the function of Fgf signaling in the zebrafish liver by expressing a dominant-negative Fgf receptor in hepatocytes (lfabp:dnfgfr1-egfp, lf:dnfr). Histological analysis showed that our genetic intervention resulted in a small liver size with defected medial expansion of developing livers in transgenic (Tg) larvae. Morphologically, the liver lobe of lf:dnfr adult fish was shorter than that of control. Ballooning degeneration of hepatocytes was observed in fish as young as 3 months. Further examination revealed the development of hepatic steatosis and cholestasis. In adult Tg fish, we unexpectedly observed increased liver-to-body-weight ratios, with higher percentages of proliferating hepatocytes. Considering all these findings, we concluded that as in mammals, in adult zebrafish the metabolism of lipid and bile acids in the liver are regulated by Fgf signaling. Disruption of the Fgf signal-mediated metabolism might indirectly affect hepatocyte proliferation. PMID:22820869

  11. Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation.

    PubMed

    Kelly, Patrick; Bailey, Candice L; Fueger, Patrick T; Newgard, Christopher B; Casey, Patrick J; Kimple, Michelle E

    2010-05-21

    Recent studies have implicated Epac2, a guanine-nucleotide exchange factor for the Rap subfamily of monomeric G proteins, as an important regulator of insulin secretion from pancreatic beta-cells. Although the Epac proteins were originally identified as cAMP-responsive activators of Rap1 GTPases, the role of Rap1 in beta-cell biology has not yet been defined. In this study, we examined the direct effects of Rap1 signaling on beta-cell biology. Using the Ins-1 rat insulinoma line, we demonstrate that activated Rap1A, but not related monomeric G proteins, promotes ribosomal protein S6 phosphorylation. Using isolated rat islets, we show that this signaling event is rapamycin-sensitive, indicating that it is mediated by the mammalian target of rapamycin complex 1-p70 S6 kinase pathway, a known growth regulatory pathway. This newly defined beta-cell signaling pathway acts downstream of cAMP, in parallel with the stimulation of cAMP-dependent protein kinase, to drive ribosomal protein S6 phosphorylation. Activated Rap1A promotes glucose-stimulated insulin secretion, islet cell hypertrophy, and islet cell proliferation, the latter exclusively through mammalian target of rapamycin complex 1, suggesting that Rap1 is an important regulator of beta-cell function. This newly defined signaling pathway may yield unique targets for the treatment of beta-cell dysfunction in diabetes. PMID:20339002

  12. NF-YA promotes invasion and angiogenesis by upregulating EZH2-STAT3 signaling in human melanoma cells.

    PubMed

    Xu, Zihan; Sun, Yaowen; Guo, Yadong; Qin, Gaoping; Mu, Shengzhi; Fan, Ronghui; Wang, Benfeng; Gao, Wenjie; Wu, Hangli; Wang, Guodong; Zhang, Zhenxin

    2016-06-01

    The process of angiogenesis is essential for tumor development and metastasis. Vascular endothelial growth factor (VEGF), which is overexpressed in most human cancers, has been demonstrated to be a major modulator of angiogenesis. Thus, inhibition of VEGF signaling has the potential for tumor anti-angiogenic therapy. Signal transducer and activator of transcription-3 (STAT3) is a key regulator for angiogenesis by directly binding to the VEGF promoter to upregulate its transcription. Several factors can enhance STAT3 activity to affect angiogenesis. Here, we found that overexpression of nuclear transcription factor-Y alpha (NF-YA) gene could promote cell invasion and angiogenesis accompanying the increase of STAT3 signaling in human melanoma cells. Moreover, the expression and secretion of VEGF was also found to be upregulated by the overexpression of NF-YA gene in melanoma cells. The STAT3 inhibitor was able to attenuate the upregulation of VEGF induced by NF-YA overexpression. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, enhances STAT3 activity by mediating its lysine methylation. We also showed that NF-YA upregulated the expression of EZH2 and NF-YA‑induced angiogenesis could be inhibited by EZH2 knockdown. Taken together, these findings indicate that overexpression of NF-YA contributes to tumor angiogenesis through EZH2-STAT3 signaling in human melanoma cells, highlighting NF-YA as a potential therapeutic target in human melanoma. PMID:27109360

  13. VCC-1, a novel chemokine, promotes tumor growth

    SciTech Connect

    Weinstein, Edward J.; Head, Richard; Griggs, David W.; Sun Duo; Evans, Robert J.; Swearingen, Michelle L.; Westlin, Marisa M.; Mazzarella, Richard . E-mail: richard.a.mazzarella@pfizer.com

    2006-11-10

    We have identified a novel human gene by transcriptional microarray analysis, which is co-regulated in tumors and angiogenesis model systems with VEGF expression. Isolation of cDNA clones containing the full-length VCC-1 transcript from both human and mouse shows a 119 amino acid protein with a 22 amino acid cleavable signal sequence in both species. Comparison of the protein product of this gene with hidden Markov models of all known proteins shows weak but significant homology with two known chemokines, SCYA17 and SCYA16. Northern analysis of human tissues detects a 1 kb band in lung and skeletal muscle. Murine VCC-1 expression can also be detected in lung as well as thyroid, submaxillary gland, epididymis, and uterus tissues by slot blot analysis. By quantitative real time RT-PCR 71% of breast tumors showed 3- to 24-fold up-regulation of VCC-1. In situ hybridization of breast carcinomas showed strong expression of the gene in both normal and transformed mammary gland ductal epithelial cells. In vitro, human microvascular endothelial cells grown on fibronectin increase VCC-1 expression by almost 100-fold. In addition, in the mouse angioma endothelial cell line PY4.1 the gene was over-expressed by 28-fold 6 h after induction of tube formation while quiescent and proliferating cells showed no change. VCC-1 expression is also increased by VEGF and FGF treatment, about 6- and 5-fold, respectively. Finally, 100% of mice injected with NIH3T3 cells over-expressing VCC-1 develop rapidly progressing tumors within 21 days while no growth is seen in any control mice injected with NIH3T3 cells containing the vector alone. These results strongly suggest that VCC-1 plays a role in angiogenesis and possibly in the development of tumors in some tissue types.

  14. The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling

    PubMed Central

    Zecchini, Silvia; Bombardelli, Lorenzo; Decio, Alessandra; Bianchi, Marco; Mazzarol, Giovanni; Sanguineti, Fabio; Aletti, Giovanni; Maddaluno, Luigi; Berezin, Vladimir; Bock, Elisabeth; Casadio, Chiara; Viale, Giuseppe; Colombo, Nicoletta; Giavazzi, Raffaella; Cavallaro, Ugo

    2011-01-01

    Epithelial ovarian carcinoma (EOC) is an aggressive neoplasm, which mainly disseminates to organs of the peritoneal cavity, an event mediated by molecular mechanisms that remain elusive. Here, we investigated the expression and functional role of neural cell adhesion molecule (NCAM), a cell surface glycoprotein involved in brain development and plasticity, in EOC. NCAM is absent from normal ovarian epithelium but becomes highly expressed in a subset of human EOC, in which NCAM expression is associated with high tumour grade, suggesting a causal role in cancer aggressiveness. We demonstrate that NCAM stimulates EOC cell migration and invasion in vitro and promotes metastatic dissemination in mice. This pro-malignant function of NCAM is mediated by its interaction with fibroblast growth factor receptor (FGFR). Indeed, not only FGFR signalling is required for NCAM-induced EOC cell motility, but targeting the NCAM/FGFR interplay with a monoclonal antibody abolishes the metastatic dissemination of EOC in mice. Our results point to NCAM-mediated stimulation of FGFR as a novel mechanism underlying EOC malignancy and indicate that this interplay may represent a valuable therapeutic target. PMID:21739604

  15. PreImplantation factor (PIF*) promotes embryotrophic and neuroprotective decidual genes: effect negated by epidermal growth factor

    PubMed Central

    2014-01-01

    Background Intimate embryo-maternal interaction is paramount for pregnancy success post-implantation. The embryo follows a specific developmental timeline starting with neural system, dependent on endogenous and decidual factors. Beyond altered genetics/epigenetics, post-natal diseases may initiate at prenatal/neonatal, post-natal period, or through a continuum. Preimplantation factor (PIF) secreted by viable embryos promotes implantation and trophoblast invasion. Synthetic PIF reverses neuroinflammation in non-pregnant models. PIF targets embryo proteins that protect against oxidative stress and protein misfolding. We report of PIF’s embryotrophic role and potential to prevent developmental disorders by regulating uterine milieu at implantation and first trimester. Methods PIF’s effect on human implantation (human endometrial stromal cells (HESC)) and first-trimester decidua cultures (FTDC) was examined, by global gene expression (Affymetrix), disease-biomarkers ranking (GeneGo), neuro-specific genes (Ingenuity) and proteins (mass-spectrometry). PIF co-cultured epidermal growth factor (EGF) in both HESC and FTDC (Affymetrix) was evaluated. Results In HESC, PIF promotes neural differentiation and transmission genes (TLX2, EPHA10) while inhibiting retinoic acid receptor gene, which arrests growth. PIF promotes axon guidance and downregulates EGF-dependent neuroregulin signaling. In FTDC, PIF promotes bone morphogenetic protein pathway (SMAD1, 53-fold) and axonal guidance genes (EPH5) while inhibiting PPP2R2C, negative cell-growth regulator, involved in Alzheimer’s and amyotrophic lateral sclerosis. In HESC, PIF affects angiotensin via beta-arrestin, transforming growth factor-beta (TGF-β), notch, BMP, and wingless-int (WNT) signaling pathways that promote neurogenesis involved in childhood neurodevelopmental diseases—autism and also affected epithelial-mesenchymal transition involved in neuromuscular disorders. In FTDC, PIF upregulates neural development

  16. Trim32 reduces PI3K-Akt-FoxO signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation.

    PubMed

    Cohen, Shenhav; Lee, Donghoon; Zhai, Bo; Gygi, Steven P; Goldberg, Alfred L

    2014-03-01

    Activation of the PI3K-Akt-FoxO pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K-Akt-FoxO signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components, including plakoglobin. In normal muscle plakoglobin binds the insulin receptor and PI3K subunit p85 and promotes PI3K-Akt-FoxO signaling. During atrophy, however, its interaction with PI3K-p85 is reduced by the ubiquitin ligase Trim32 (tripartite motif containing protein 32). Inhibition of Trim32 enhanced plakoglobin binding to PI3K-p85 and promoted PI3K-Akt-FoxO signaling. Surprisingly, plakoglobin overexpression alone enhanced PI3K-Akt-FoxO signaling. Furthermore, Trim32 inhibition in normal muscle increased PI3K-Akt-FoxO signaling, enhanced glucose uptake, and induced fiber growth, whereas plakoglobin down-regulation reduced PI3K-Akt-FoxO signaling, decreased glucose uptake, and caused atrophy. Thus, by promoting plakoglobin-PI3K dissociation, Trim32 reduces PI3K-Akt-FoxO signaling in normal and atrophying muscle. This mechanism probably contributes to insulin resistance during fasting and catabolic diseases and perhaps to the myopathies and cardiomyopathies seen with Trim32 and plakoglobin mutations. PMID:24567360

  17. Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression.

    PubMed

    da Silva-Diz, Victoria; Simón-Extremera, Pilar; Bernat-Peguera, Adrià; de Sostoa, Jana; Urpí, Maria; Penín, Rosa M; Sidelnikova, Diana Pérez; Bermejo, Oriol; Viñals, Joan Maria; Rodolosse, Annie; González-Suárez, Eva; Moruno, Antonio Gómez; Pujana, Miguel Ángel; Esteller, Manel; Villanueva, Alberto; Viñals, Francesc; Muñoz, Purificación

    2016-03-01

    Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. β-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC. PMID:26719534

  18. A Trypanosoma brucei Kinesin Heavy Chain Promotes Parasite Growth by Triggering Host Arginase Activity

    PubMed Central

    De Muylder, Géraldine; Daulouède, Sylvie; Lecordier, Laurence; Uzureau, Pierrick; Morias, Yannick; Van Den Abbeele, Jan; Caljon, Guy; Hérin, Michel; Holzmuller, Philippe; Semballa, Silla; Courtois, Pierrette; Vanhamme, Luc; Stijlemans, Benoît; De Baetselier, Patrick; Barrett, Michael P.; Barlow, Jillian L.; McKenzie, Andrew N. J.; Barron, Luke; Wynn, Thomas A.; Beschin, Alain; Vincendeau, Philippe; Pays, Etienne

    2013-01-01

    Background In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells. Methodology/Principal findings By screening a cDNA library of T. brucei with an antibody neutralizing the arginase-inducing activity of parasite released factors, we identified a Kinesin Heavy Chain isoform, termed TbKHC1, as responsible for this effect. Following interaction with mouse myeloid cells, natural or recombinant TbKHC1 triggered SIGN-R1 receptor-dependent induction of IL-10 production, resulting in arginase-1 activation concomitant with reduction of nitric oxide (NO) synthase activity. This TbKHC1 activity was IL-4Rα-independent and did not mirror M2 activation of myeloid cells. As compared to wild-type T. brucei, infection by TbKHC1 KO parasites was characterized by strongly reduced parasitaemia and prolonged host survival time. By treating infected mice with ornithine or with NO synthase inhibitor, we observed that during the first wave of parasitaemia the parasite growth-promoting effect of TbKHC1-mediated arginase activation resulted more from increased polyamine production than from reduction of NO synthesis. In late stage infection, TbKHC1-mediated reduction of NO synthesis appeared to contribute to liver damage linked to shortening of host survival time. Conclusion A kinesin heavy chain released by T. brucei induces IL-10 and arginase-1 through SIGN-R1 signaling in myeloid cells, which promotes early trypanosome growth and favors parasite settlement in the host. Moreover, in the late stage of infection, the inhibition of NO synthesis by TbKHC1 contributes to liver pathogenicity. PMID:24204274

  19. Fas signaling promotes chemoresistance in gastrointestinal cancer by up-regulating P-glycoprotein

    PubMed Central

    Wang, Yadong; Lin, Shiyong; Chen, Jinmin; Wang, Jing; Wang, Zhiqing; Jiang, Bo

    2014-01-01

    Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing β-catenin and decreasing miR-145. β-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3′UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, β-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P-gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by β-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance. PMID:25333257

  20. Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells

    PubMed Central

    Zhao, Jingshan; Niu, Honglin; Li, Aiying; Nie, Lei

    2016-01-01

    The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL), a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF) signaling and angiogenesis in endothelial cells (ECs). We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day) recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis. PMID:26863518

  1. Hpa1 harpin needs nitroxyl terminus to promote vegetative growth and leaf photosynthesis in Arabidopsis.

    PubMed

    Li, Xiaojie; Han, Liping; Zhao, Yanying; You, Zhenzhen; Dong, Hansong; Zhang, Chunling

    2014-03-01

    Hpa1 is a harpin protein produced by Xanthomonas oryzae, an important bacterial pathogen of rice, and has the growth-promoting activity in plants. To understand the molecular basis for the function of Hpa1, we generated an inactive variant protein, Hpa1 delta NT, by deleting the nitroxyl-terminal region of the Hpa1 sequence and compared Hpa1 delta NT with the full-length protein in terms of the effects on vegetative growth and related physiological responses in Arabidopsis. When Hpa1 was applied to plants, it acted to enhance the vegetative growth but did not affect the floral development. Enhanced plant growth was accompanied by induced expression of growth-promoting genes in plant leaves. The growth-promoting activity of Hpa1 was further correlated with a physiological consequence shown as promoted leaf photosynthesis as a result of facilitated CO2 conduction through leaf stomata and mesophyll cells. On the contrary, plant growth, growth-promoting gene expression, and the physiological consequence changed little in response to the Hpa1 delta NT treatment. These analyses suggest that Hpa1 requires the nitroxyl-terminus to facilitate CO2 transport inside leaf cells and promote leaf photosynthesis and vegetative growth of the plant. PMID:24499797

  2. The suppressor of cytokine signaling SOCS1 promotes apoptosis of intestinal epithelial cells via p53 signaling in Crohn's disease.

    PubMed

    Cui, Xiaopeng; Shan, Xiaohang; Qian, Ji; Ji, Qianqian; Wang, Liang; Wang, Xiaotong; Li, Manhua; Ding, Haifang; Liu, Qingqing; Chen, Lingling; Zhang, Dongmei; Ni, Runzhou

    2016-08-01

    The suppressor of cytokine signaling SOCS1 is a member of the cytokine signaling pathway inhibitor family, which is induced by the IFN-γ induced JAK signaling pathway. The expression of SOCS1 has been found to increase in Crohn's disease (CD) patients, but the role of SOCS1 in intestinal epithelium is unclear. This study was designed to investigate whether SOCS1 has a role in the death of intestinal epithelial cells and intestinal injury. The results showed that the expression of SOCS1 increased in CD patients, and the expression of SOCS1, p-p53 and PUMA increased in the mouse TNBS induced colitis model. Using IFN-γ treated HT-29 cells as an apoptotic model of intestinal epithelial cells in vitro, we confirmed that SOCS1 promoted apoptosis of intestinal epithelial cells by activating p53. In HT-29 cells which were treated with IFN-γ, the interaction between p53 and SOCS1 and phosphorylation of p53 were significantly higher than untreated cells. When knocking SOCS1 down by using SOCS1 siRNA, phosphorylation of p53 and apoptosis of intestinal epithelial cells which was induced by IFN-γ were significantly inhibited. In summary, our findings suggest that SOCS1 may promote apoptosis of intestinal epithelial cells at least partly through mediating p53 signaling. PMID:27236107

  3. Beta-nerve growth factor promotes neurogenesis and angiogenesis during the repair of bone defects

    PubMed Central

    Chen, Wei-hui; Mao, Chuan-qing; Zhuo, Li-li; Ong, Joo L.

    2015-01-01

    We previously showed that the repair of bone defects is regulated by neural and vascular signals. In the present study, we examined the effect of topically applied β-nerve growth factor (β-NGF) on neurogenesis and angiogenesis in critical-sized bone defects filled with collagen bone substitute. We created two symmetrical defects, 2.5 mm in diameter, on either side of the parietal bone of the skull, and filled them with bone substitute. Subcutaneously implanted osmotic pumps were used to infuse 10 μg β-NGF in PBS (β-NGF + PBS) into the right-hand side defect, and PBS into the left (control) defect, over the 7 days following surgery. Immunohistochemical staining and hematoxylin-eosin staining were carried out at 3, 7, 14, 21 and 28 days postoperatively. On day 7, expression of β III-tubulin was lower on the β-NGF + PBS side than on the control side, and that of neurofilament 160 was greater. On day 14, β III-tubulin and protein gene product 9.5 were greater on the β-NGF + PBS side than on the control side. Vascular endothelial growth factor expression was greater on the experimental side than the control side at 7 days, and vascular endothelial growth factor receptor 2 expression was elevated on days 14 and 21, but lower than control levels on day 28. However, no difference in the number of blood vessels was observed between sides. Our results indicate that topical application of β-NGF promoted neurogenesis, and may modulate angiogenesis by promoting nerve regeneration in collagen bone substitute-filled defects. PMID:26330843

  4. Inhibition of diacylglycerol kinases as a physiological way to promote diacylglycerol signaling.

    PubMed

    Baldanzi, Gianluca

    2014-05-01

    Diacylglycerol is a key regulator of cell physiology, controlling the membrane recruitment and activation of signaling molecules. Accordingly, diacylglycerol generation and metabolism are strictly controlled, allowing for localized regulation of its concentration. While the increased production of diacylglycerol upon receptor triggering is well recognized, the modulation of diacylglycerol metabolism by diacylglycerol kinases (DGKs) is less characterized. Some agonists induce DGK activation and recruitment to the plasma membrane, promoting diacylglycerol metabolism to phosphatidic acid. Conversely, several reports indicate that signaling pathways that selectively inhibits DGK isoforms can enhance cellular diacylglycerol levels and signal transduction. For example, the impairment of DGKθ activity by RhoA binding to the catalytic domain represents a conserved mechanism controlling diacylglycerol signaling from Caenorhabditis elegans motoneurons to mammalian hepatocytes. Similarly, DGKα activity is inhibited in lymphocytes by TCR signaling, thus contributing to a rise in diacylglycerol concentration for downstream signaling. Finally, DGKμ activity is inhibited by ischemia-reperfusion-generated reactive oxygen species in airway endothelial cells, promoting diacylglycerol-mediated ion channel opening and edema. In those systems, DGKs provide a gatekeeper function by blunting diacylglycerol levels or possibly establishing permissive domains for diacylglycerol signaling. In this review, I discuss the possible general relevance of DGK inhibition to enhanced diacylglycerol signaling. PMID:24582387

  5. Resveratrol augments the canonical Wnt signaling pathway in promoting osteoblastic differentiation of multipotent mesenchymal cells

    SciTech Connect

    Zhou, Haibin; Shang, Linshan; Li, Xi; Zhang, Xiyu; Gao, Guimin; Guo, Chenhong; Chen, Bingxi; Liu, Qiji; Gong, Yaoqin; Shao, Changshun

    2009-10-15

    Resveratrol has been shown to possess many health-benefiting effects, including the promotion of bone formation. In this report we investigated the mechanism by which resveratrol promotes osteoblastic differentiation from pluripotent mesenchymal cells. Since Wnt signaling is well documented to induce osteoblastogenesis and bone formation, we characterized the factors involved in Wnt signaling in response to resveratrol treatment. Resveratrol treatment of mesenchymal cells led to an increase in stabilization and nuclear accumulation of {beta}-catenin dose-dependently and time-dependently. As a consequence of the increased nuclear accumulation of {beta}-catenin, the ability to activate transcription of {beta}-catenin-TCF/LEF target genes that are required for osteoblastic differentiation was upregulated. However, resveratrol did not affect the initial step of the Wnt signaling pathway, as resveratrol was as effective in upregulating the activity of {beta}-catenin in cells in which Lrp5 was knocked down as in control cells. In addition, while conditioned medium enriched in Wnt signaling antagonist Dkk1 was able to inhibit Wnt3a-induced {beta}-catenin upregulation, this inhibitory effect can be abolished in resveratrol-treated cells. Furthermore, we showed that the level of glycogen synthase kinase 3{beta} (GSK-3{beta}), which phosphorylates and destabilizes {beta}-catenin, was reduced in response to resveratrol treatment. The phosphorylation of GSK-3{beta} requires extracellular signal-regulated kinase (ERK)1/2. Together, our data indicate that resveratrol promotes osteoblastogenesis and bone formation by augmenting Wnt signaling.

  6. Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma

    PubMed Central

    Andersen, Nicholas J.; Nickoloff, Brian J.; Dykema, Karl J.; Boguslawski, Elissa A.; Krivochenitser, Roman I.; Froman, Roe E.; Dawes, Michelle J.; Baker, Laurence H.; Thomas, Dafydd G.; Kamstock, Debra A.; Kitchell, Barbara E.; Furge, Kyle A.; Duesbery, Nicholas S.

    2013-01-01

    Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human AS, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive ERK activation. The MEK inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multi-receptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human AS, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was up-regulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human AS. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human AS, and it highlights the utility of spontaneous canine cancers as a model of human disease. PMID:23804705

  7. Early Acceleration of Students in Mathematics: Does It Promote Growth and Stability of Growth in Achievement across Mathematical Areas?

    ERIC Educational Resources Information Center

    Ma, Xin

    2005-01-01

    Using data from the Longitudinal Study of American Youth (LSAY), the present study examined whether early acceleration of students into formal algebra at the beginning of middle school promoted evident growth in different mathematical areas (basic skills, algebra, geometry, and quantitative literacy) and stable growth across these mathematical…

  8. Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF-β signaling pathway inhibition.

    PubMed

    Zuo, Zu-Qi; Chen, Kai-Ge; Yu, Xiao-Yuan; Zhao, Gui; Shen, Song; Cao, Zhi-Ting; Luo, Ying-Li; Wang, Yu-Cai; Wang, Jun

    2016-03-01

    Cancer stem cells (CSCs), which hold a high capacity for self-renewal, play a central role in the development, metastasis, and recurrence of various malignancies. CSCs must be eradicated to cure instances of cancer; however, because they can reside far from tumor vessels, they are not easily targeted by drug agents carried by nanoparticle-based drug delivery systems. We herein demonstrate that promoting tumor penetration of nanoparticles by transforming growth factor β (TGF-β) signaling pathway inhibition facilitates CSC therapy. In our study, we observed that although nanoparticles carrying siRNA targeting the oncogene polo-like kinase 1 (Plk1) efficiently killed breast CSCs derived from MDA-MB-231 cells in vitro, this intervention enriched CSCs in the residual tumor tissue following systemic treatment. However, inhibition of the TGF-β signaling pathway with LY364947, an inhibitor of TGF-β type I receptor, promoted the penetration of nanoparticles in tumor tissue, significantly ameliorating the intratumoral distribution of nanoparticles in MDA-MB-231 xenografts and further leading to enhanced internalization of nanoparticles by CSCs. As a result, synergistic treatment with a nanoparticle drug delivery system and LY364947 inhibited tumor growth and reduced the proportion of CSCs in vivo. This study suggests that enhanced tumor penetration of drug-carrying nanoparticles can enhance CSCs clearance in vivo and consequently provide superior anti-tumor effects. PMID:26751819

  9. The promoting effects of alginate oligosaccharides on root development in Oryza sativa L. mediated by auxin signaling.

    PubMed

    Zhang, Yunhong; Yin, Heng; Zhao, Xiaoming; Wang, Wenxia; Du, Yuguang; He, Ailing; Sun, Kegang

    2014-11-26

    Alginate oligosaccharides (AOS), which are marine oligosaccharides, are involved in regulating plant root growth, but the promotion mechanism for AOS remains unclear. Here, AOS (10-80 mg/L) induced the expression of auxin-related gene (OsYUCCA1, OsYUCCA5, OsIAA11 and OsPIN1) in rice (Oryza sativa L.) tissues to accelerate auxin biosynthesis and transport, and reduced indole-3-acetic acid (IAA) oxidase activity in rice roots. These changes resulted in the increase of 37.8% in IAA concentration in rice roots, thereby inducing the expression of root development-related genes, promoting root growth in a dose-dependent manner, which were inhibited by auxin transport inhibitor 2,3,5-triiodo benzoic acid (TIBA) and calcium-chelating agent ethylene glycol bis (2-aminoethyl) tetraacetic acid (EGTA). AOS also induced calcium signaling generation in rice roots. Those results indicated that auxin mediated AOS regulation of root development, and calcium signaling may act mainly in the upstream of auxin in the regulation of AOS on rice root development. PMID:25256506

  10. Endodermal ABA Signaling Promotes Lateral Root Quiescence during Salt Stress in Arabidopsis Seedlings[C][W

    PubMed Central

    Duan, Lina; Dietrich, Daniela; Ng, Chong Han; Chan, Penny Mei Yeen; Bhalerao, Rishikesh; Bennett, Malcolm J.; Dinneny, José R.

    2013-01-01

    The endodermal tissue layer is found in the roots of vascular plants and functions as a semipermeable barrier, regulating the transport of solutes from the soil into the vascular stream. As a gateway for solutes, the endodermis may also serve as an important site for sensing and responding to useful or toxic substances in the environment. Here, we show that high salinity, an environmental stress widely impacting agricultural land, regulates growth of the seedling root system through a signaling network operating primarily in the endodermis. We report that salt stress induces an extended quiescent phase in postemergence lateral roots (LRs) whereby the rate of growth is suppressed for several days before recovery begins. Quiescence is correlated with sustained abscisic acid (ABA) response in LRs and is dependent upon genes necessary for ABA biosynthesis, signaling, and transcriptional regulation. We use a tissue-specific strategy to identify the key cell layers where ABA signaling acts to regulate growth. In the endodermis, misexpression of the ABA insensitive1-1 mutant protein, which dominantly inhibits ABA signaling, leads to a substantial recovery in LR growth under salt stress conditions. Gibberellic acid signaling, which antagonizes the ABA pathway, also acts primarily in the endodermis, and we define the crosstalk between these two hormones. Our results identify the endodermis as a gateway with an ABA-dependent guard, which prevents root growth into saline environments. PMID:23341337

  11. Beyond the brain-Peripheral kisspeptin signaling is essential for promoting endometrial gland development and function

    PubMed Central

    León, Silvia; Fernadois, Daniela; Sull, Alexandra; Sull, Judith; Calder, Michele; Hayashi, Kanako; Bhattacharya, Moshmi; Power, Stephen; Vilos, George A.; Vilos, Angelos G.; Tena-Sempere, Manuel; Babwah, Andy V.

    2016-01-01

    Uterine growth and endometrial gland formation (adenogenesis) and function, are essential for fertility and are controlled by estrogens and other regulators, whose nature and physiological relevance are yet to be elucidated. Kisspeptin, which signals via Kiss1r, is essential for fertility, primarily through its central control of the hypothalamic-pituitary-ovarian axis, but also likely through peripheral actions. Using genetically modified mice, we addressed the contributions of central and peripheral kisspeptin signaling in regulating uterine growth and adenogenesis. Global ablation of Kiss1 or Kiss1r dramatically suppressed uterine growth and almost fully prevented adenogenesis. However, while uterine growth was fully rescued by E2 treatment of Kiss1−/− mice and by genetic restoration of kisspeptin signaling in GnRH neurons in Kiss1r−/− mice, functional adenogenesis was only marginally restored. Thus, while uterine growth is largely dependent on ovarian E2-output via central kisspeptin signaling, peripheral kisspeptin signaling is indispensable for endometrial adenogenesis and function, essential aspects of reproductive competence. PMID:27364226

  12. Beyond the brain-Peripheral kisspeptin signaling is essential for promoting endometrial gland development and function.

    PubMed

    León, Silvia; Fernadois, Daniela; Sull, Alexandra; Sull, Judith; Calder, Michele; Hayashi, Kanako; Bhattacharya, Moshmi; Power, Stephen; Vilos, George A; Vilos, Angelos G; Tena-Sempere, Manuel; Babwah, Andy V

    2016-01-01

    Uterine growth and endometrial gland formation (adenogenesis) and function, are essential for fertility and are controlled by estrogens and other regulators, whose nature and physiological relevance are yet to be elucidated. Kisspeptin, which signals via Kiss1r, is essential for fertility, primarily through its central control of the hypothalamic-pituitary-ovarian axis, but also likely through peripheral actions. Using genetically modified mice, we addressed the contributions of central and peripheral kisspeptin signaling in regulating uterine growth and adenogenesis. Global ablation of Kiss1 or Kiss1r dramatically suppressed uterine growth and almost fully prevented adenogenesis. However, while uterine growth was fully rescued by E2 treatment of Kiss1(-/-) mice and by genetic restoration of kisspeptin signaling in GnRH neurons in Kiss1r(-/-) mice, functional adenogenesis was only marginally restored. Thus, while uterine growth is largely dependent on ovarian E2-output via central kisspeptin signaling, peripheral kisspeptin signaling is indispensable for endometrial adenogenesis and function, essential aspects of reproductive competence. PMID:27364226

  13. Prostaglandin F2α receptor (FP) signaling regulates Bmp signaling and promotes chondrocyte differentiation

    PubMed Central

    Kim, Joohwee; Shim, Minsub

    2015-01-01

    Prostaglandins are a group of lipid signaling molecules involved in various physiological processes. In addition, prostaglandins have been implicated in the development and progression of diseases including cancer, cardiovascular disease, and arthritis. Prostaglandins exert their effects through the activation of specific G protein-coupled receptors (GPCRs). In this report, we examined the role of prostaglandin F2α receptor (FP) signaling as a regulator of chondrocyte differentiation. We found that FP expression was dramatically induced during the differentiation of chondrocytes and was up-regulated in cartilages. Forced expression of FP in ATDC5 chondrogenic cell line resulted in the increased expression of differentiation-related genes and increased synthesis of the extracellular matrix (ECM) regardless of the presence of insulin. Similarly, PGF2α treatment induced the expression of chondrogenic marker genes. In contrast, knockdown of endogenous FP expression suppressed the expression of chondrocyte marker genes and ECM synthesis. Organ culture of cartilage rudiments revealed that PGF2α induces chondrocyte hypertrophy. Additionally, FP overexpression increased the levels of Bmp-6, phospho-Smad1/5, and Bmpr1a, while knockdown of FP reduced expression of those genes. These results demonstrate that up-regulation of FP expression plays an important role in chondrocyte differentiation and modulates Bmp signaling. PMID:25499765

  14. Notch signaling indirectly promotes chondrocyte hypertrophy via regulation of BMP signaling and cell cycle arrest

    PubMed Central

    Shang, Xifu; Wang, Jinwu; Luo, Zhengliang; Wang, Yongjun; Morandi, Massimo M.; Marymont, John V.; Hilton, Matthew J.; Dong, Yufeng

    2016-01-01

    Cell cycle regulation is critical for chondrocyte differentiation and hypertrophy. Recently we identified the Notch signaling pathway as an important regulator of chondrocyte proliferation and differentiation during mouse cartilage development. To investigate the underlying mechanisms, we assessed the role for Notch signaling regulation of the cell cycle during chondrocyte differentiation. Real-time RT-PCR data showed that over-expression of the Notch Intracellular Domain (NICD) significantly induced the expression of p57, a cell cycle inhibitor, in chondrocytes. Flow cytometric analyses further confirmed that over-expression of NICD in chondrocytes enhances the G0/G1 cell cycle transition and cell cycle arrest. In contrast, treatment of chondrocytes with the Notch inhibitor, DAPT, decreased both endogenous and BMP2-induced SMAD 1/5/8 phosphorylation and knockdown of SMAD 1/5/8 impaired NICD-induced chondrocyte differentiation and p57 expression. Co-immunoprecipitation using p-SMAD 1/5/8 and NICD antibodies further showed a strong interaction of these proteins during chondrocyte maturation. Finally, RT-PCR and Western blot results revealed a significant reduction in the expression of the SMAD-related phosphatase, PPM1A, following NICD over-expression. Taken together, our results demonstrate that Notch signaling induces cell cycle arrest and thereby initiates chondrocyte hypertrophy via BMP/SMAD-mediated up-regulation of p57. PMID:27146698

  15. Zinc promotes proliferation and activation of myogenic cells via the PI3K/Akt and ERK signaling cascade

    SciTech Connect

    Ohashi, Kazuya; Nagata, Yosuke; Wada, Eiji; Zammit, Peter S.; Shiozuka, Masataka; Matsuda, Ryoichi

    2015-05-01

    Skeletal muscle stem cells named muscle satellite cells are normally quiescent but are activated in response to various stimuli, such as injury and overload. Activated satellite cells enter the cell cycle and proliferate to produce a large number of myogenic progenitor cells, and these cells then differentiate and fuse to form myofibers. Zinc is one of the essential elements in the human body, and has multiple roles, including cell growth and DNA synthesis. However, the role of zinc in myogenic cells is not well understood, and is the focus of this study. We first examined the effects of zinc on differentiation of murine C2C12 myoblasts and found that zinc promoted proliferation, with an increased number of cells incorporating EdU, but inhibited differentiation with reduced myogenin expression and myotube formation. Furthermore, we used the C2C12 reserve cell model of myogenic quiescence to investigate the role of zinc on activation of myogenic cells. The number of reserve cells incorporating BrdU was increased by zinc in a dose dependent manner, with the number dramatically further increased using a combination of zinc and insulin. Akt and extracellular signal-regulated kinase (ERK) are downstream of insulin signaling, and both were phosphorylated after zinc treatment. The zinc/insulin combination-induced activation involved the phosphoinositide 3-kinase (PI3K)/Akt and ERK cascade. We conclude that zinc promotes activation and proliferation of myogenic cells, and this activation requires phosphorylation of PI3K/Akt and ERK as part of the signaling cascade. - Highlights: • Zinc has roles for promoting proliferation and inhibition differentiation of C2C12. • Zinc promotes activation of reserve cells. • Insulin and zinc synergize activation of reserve cells. • PI3K/Akt and ERK cascade affect zinc/insulin-mediated activation of reserve cells.

  16. The organochlorine p,p'-dichlorodiphenyltrichloroethane induces colorectal cancer growth through Wnt/β-catenin signaling.

    PubMed

    Song, Li; Zhao, Junyu; Jin, Xiaoting; Li, Zhuoyu; Newton, Ian P; Liu, Weiping; Xiao, Hong; Zhao, Meirong

    2014-08-17

    Dichlorodiphenyltrichloroethane (DDT), an organochlorine pollutant, is associated with several types of cancer. However, the relationship between DDT and colorectal cancer is uncertain. In this study, the impact of p,p'-DDT on colorectal cancer growth was evaluated using both in vitro and in vivo models. Our results indicated that the proliferation of human colorectal adenocarcinoma DLD1 cells was significantly promoted after exposed to low concentrations of p,p'-DDT ranging from 10(-12) to 10(-7) M for 96 h. Exposure to p,p'-DDT from 10(-10) to 10(-8) M led to upregulation of phospho-GSK3β (Ser9), β-catenin, c-Myc and cyclin D1 in DLD1 cells. RNA interference of β-catenin inhibited the proliferation of DLD1 cells stimulated by p,p'-DDT. Inhibiting of estrogen receptors (ERs) had no significant effect on the action of p,p'-DDT. Treatment with p,p'-DDT induced production of intracellular reactive oxygen species (ROS) and inhibited superoxide dismutase (SOD) activity in DLD1 cells. Treatment with N-acetyl-L-cysteine (NAC), a ROS inhibitor, suppressed the induction of Wnt/β-catenin signaling and DLD1 cell proliferation by p,p'-DDT. Moreover, in a mouse xenograft model, 5 nmol/kg p,p'-DDT resulted in increased tumor size, oxidative stress and Wnt/β-catenin signaling. These results indicated that low concentrations of p,p'-DDT promoted colorectal cancer growth through Wnt/β-catenin signaling, which was mediated by oxidative stress. The finding suggests an association between low concentrations of p,p'-DDT exposure and colorectal cancer progression. PMID:24968063

  17. Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1.

    PubMed

    Shao, H; Cai, L; Grichnik, J M; Livingstone, A S; Velazquez, O C; Liu, Z-J

    2011-10-20

    The tumor microenvironment is emerging as an important target for cancer therapy. Fibroblasts (Fbs) within the tumor stroma are critically involved in promoting tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix and direct cell-cell interaction. In this work, we aim to alter the biological activity of stromal Fbs by modulating the Notch1 signaling pathway. We show that Fbs engineered to constitutively activate the Notch1 pathway significantly inhibit melanoma growth and tumor angiogenesis. We determine that the inhibitory effect of 'Notch-engineered' Fbs is mediated by increased secretion of Wnt-induced secreted protein-1 (WISP-1) as the effects of Notch1 activation in Fbs are reversed by shRNA-mediated blockade of WISP-1. When 'Notch-engineered' Fbs are co-grafted with melanoma cells in SCID mice, shRNA-mediated blockade of WISP-1 reverses the tumor-suppressive phenotype of the 'Notch-engineered' Fbs, significantly increases melanoma growth and tumor angiogenesis. Consistent with these findings, supplement of recombinant WISP-1 protein inhibits melanoma cell growth in vitro. In addition, WISP-1 is modestly expressed in melanoma-activated Fbs but highly expressed in inactivated Fbs. Evaluation of human melanoma skin biopsies indicates that expression of WISP-1 is significantly lower in melanoma nests and surrounding areas filled with infiltrated immune cells than in the adjacent dermis unaffected by the melanoma. Overall, our study shows that constitutive activation of the Notch1 pathway confers Fbs with a suppressive phenotype to melanoma growth, partially through WISP-1. Thus, targeting tumor stromal Fbs by activating Notch signaling and/or increasing WISP-1 may represent a novel therapeutic approach to combat melanoma. PMID:21516124

  18. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.

    PubMed

    Moll, Lorna; Ben-Gedalya, Tziona; Reuveni, Hadas; Cohen, Ehud

    2016-04-01

    The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. PMID:26722006

  19. TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons

    PubMed Central

    Kandasamy, Mahesh; Lehner, Bernadette; Kraus, Sabrina; Sander, Paul Ramm; Marschallinger, Julia; Rivera, Francisco J; Trümbach, Dietrich; Ueberham, Uwe; Reitsamer, Herbert A; Strauss, Olaf; Bogdahn, Ulrich; Couillard-Despres, Sebastien; Aigner, Ludwig

    2014-01-01

    Members of the transforming growth factor (TGF)-β family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF-β signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-β1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-β1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-β1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-β1 signalling in adult NPCs. The results demonstrate that TGF-β1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF-β1 in ageing and neurodegenerative diseases, TGF-β1 signalling presents a molecular target for future interventions in such conditions. PMID:24779367

  20. TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons.

    PubMed

    Kandasamy, Mahesh; Lehner, Bernadette; Kraus, Sabrina; Sander, Paul Ramm; Marschallinger, Julia; Rivera, Francisco J; Trümbach, Dietrich; Ueberham, Uwe; Reitsamer, Herbert A; Strauss, Olaf; Bogdahn, Ulrich; Couillard-Despres, Sebastien; Aigner, Ludwig

    2014-07-01

    Members of the transforming growth factor (TGF)-β family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF-β signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-β1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-β1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-β1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-β1 signalling in adult NPCs. The results demonstrate that TGF-β1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF-β1 in ageing and neurodegenerative diseases, TGF-β1 signalling presents a molecular target for future interventions in such conditions. PMID:24779367

  1. Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling

    PubMed Central

    North, Hilary A.; Zhao, Xiumei; Kolk, Sharon M.; Clifford, Meredith A.; Ziskind, Daniela M.; Donoghue, Maria J.

    2009-01-01

    Summary Eph receptors are widely expressed during cerebral cortical development, yet a role for Eph signaling in the generation of cells during corticogenesis has not been shown. Cortical progenitor cells selectively express one receptor, EphA4, and reducing EphA4 signaling in cultured progenitors suppressed proliferation, decreasing cell number. In vivo, EphA4-/- cortex had a reduced area, fewer cells and less cell division compared with control cortex. To understand the effects of EphA4 signaling in corticogenesis, EphA4-mediated signaling was selectively depressed or elevated in cortical progenitors in vivo. Compared with control cells, cells with reduced EphA4 signaling were rare and mitotically inactive. Conversely, overexpression of EphA4 maintained cells in their progenitor states at the expense of subsequent maturation, enlarging the progenitor pool. These results support a role for EphA4 in the autonomous promotion of cell proliferation during corticogenesis. Although most ephrins were undetectable in cortical progenitors, ephrin B1 was highly expressed. Our analyses demonstrate that EphA4 and ephrin B1 bind to each other, thereby initiating signaling. Furthermore, overexpression of ephrin B1 stimulated cell division of neighboring cells, supporting the hypothesis that ephrin B1-initiated forward signaling of EphA4 promotes cortical cell division. PMID:19542359

  2. Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation.

    PubMed

    Horbelt, Daniel; Boergermann, Jan H; Chaikuad, Apirat; Alfano, Ivan; Williams, Eleanor; Lukonin, Ilya; Timmel, Tobias; Bullock, Alex N; Knaus, Petra

    2015-02-01

    GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis. PMID:25368322

  3. Phosphatidic acid-mediated activation and translocation to the cell surface of sialidase NEU3, promoting signaling for cell migration.

    PubMed

    Shiozaki, Kazuhiro; Takahashi, Kohta; Hosono, Masahiro; Yamaguchi, Kazunori; Hata, Keiko; Shiozaki, Momo; Bassi, Rosaria; Prinetti, Alessandro; Sonnino, Sandro; Nitta, Kazuo; Miyagi, Taeko

    2015-05-01

    The plasma membrane-associated sialidase NEU3 plays crucial roles in regulation of transmembrane signaling, and its aberrant up-regulation in various cancers contributes to malignancy. However, it remains uncertain how NEU3 is naturally activated and locates to plasma membranes, because of its Triton X-100 requirement for the sialidase activity in vitro and its often changing subcellular location. Among phospholipids examined, we demonstrate that phosphatidic acid (PA) elevates its sialidase activity 4 to 5 times at 50 μM in vitro at neutral pH and promotes translocation to the cell surface and cell migration through Ras-signaling in HeLa and COS-1 cells. NEU3 was found to interact selectively with PA as assessed by phospholipid array, liposome coprecipitation, and ELISA assays and to colocalize with phospholipase D (PLD) 1 in response to epidermal growth factor (EGF) or serum stimulation. Studies using tagged NEU3 fragments with point mutations identified PA- and calmodulin (CaM)-binding sites around the N terminus and confirmed its participation in translocation and catalytic activity. EGF induced PLD1 activation concomitantly with enhanced NEU3 translocation to the cell surface, as assessed by confocal microscopy. These results suggest that interactions of NEU3 with PA produced by PLD1 are important for regulation of transmembrane signaling, this aberrant acceleration probably promoting malignancy in cancers. PMID:25678627

  4. Small Molecules Dorsomorphin and LDN-193189 Inhibit Myostatin/GDF8 Signaling and Promote Functional Myoblast Differentiation*

    PubMed Central

    Horbelt, Daniel; Boergermann, Jan H.; Chaikuad, Apirat; Alfano, Ivan; Williams, Eleanor; Lukonin, Ilya; Timmel, Tobias; Bullock, Alex N.; Knaus, Petra

    2015-01-01

    GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis. PMID:25368322

  5. EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells

    PubMed Central

    Castanieto, Angela; Johnston, Michael J; Nystul, Todd G

    2014-01-01

    Epithelial stem cells divide asymmetrically, such that one daughter replenishes the stem cell pool and the other differentiates. We found that, in the epithelial follicle stem cell (FSC) lineage of the Drosophila ovary, epidermal growth factor receptor (EGFR) signaling functions specifically in the FSCs to promote the unique partially polarized state of the FSC, establish apical–basal polarity throughout the lineage, and promote FSC maintenance in the niche. In addition, we identified a novel connection between EGFR signaling and the cell-polarity regulator liver kinase B1 (LKB1), which indicates that EGFR signals through both the Ras–Raf–MEK–Erk pathway and through the LKB1–AMPK pathway to suppress apical identity. The development of apical–basal polarity is the earliest visible difference between FSCs and their daughters, and our findings demonstrate that the EGFR-mediated regulation of apical–basal polarity is essential for the segregation of stem cell and daughter cell fates. DOI: http://dx.doi.org/10.7554/eLife.04437.001 PMID:25437306

  6. RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

    PubMed Central

    Seo, Mihwa; Seo, Keunhee; Hwang, Wooseon; Koo, Hee Jung; Hahm, Jeong-Hoon; Yang, Jae-Seong; Han, Seong Kyu; Hwang, Daehee; Kim, Sanguk; Jang, Sung Key; Lee, Yoontae; Nam, Hong Gil; Lee, Seung-Jae V.

    2015-01-01

    The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans. PMID:26195740

  7. RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans.

    PubMed

    Seo, Mihwa; Seo, Keunhee; Hwang, Wooseon; Koo, Hee Jung; Hahm, Jeong-Hoon; Yang, Jae-Seong; Han, Seong Kyu; Hwang, Daehee; Kim, Sanguk; Jang, Sung Key; Lee, Yoontae; Nam, Hong Gil; Lee, Seung-Jae V

    2015-08-01

    The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans. PMID:26195740

  8. Plant growth-promoting rhizobacteria strain Bacillus amyloliquefaciens NJN-6-enriched bio-organic fertilizer suppressed Fusarium wilt and promoted the growth of banana plants.

    PubMed

    Yuan, Jun; Ruan, Yunze; Wang, Beibei; Zhang, Jian; Waseem, Raza; Huang, Qiwei; Shen, Qirong

    2013-04-24

    Bacillus amyloliquefaciens strain NJN-6 is an important plant growth-promoting rhizobacteria (PGPR) which can produce secondary metabolites antagonistic to several soil-borne pathogens. In this study, the ability of a bio-organic fertilizer (BIO) containing NJN-6 strain to promote the growth and suppress Fusarium wilt of banana plants was evaluated in a pot experiment. The results showed that the application of BIO significantly decreased the incidence of Fusarium wilt and promoted the growth of banana plants compared to that for the organic fertilizer (OF). To determine the beneficial mechanism of the strain, the colonization of NJN-6 strain on banana roots was evaluated using scanning electron microscopy (SEM). The plant growth-promoting hormones indole-3-acetic acid (IAA) and gibberellin A3 (GA3), along with antifungal lipopeptides iturin A, were detected when the NJN-6 strain was incubated in both Landy medium with additional l-tryptophan and in root exudates of banana plants. In addition, some antifungal volatile organic compounds and iturin A were also detected in BIO. In summary, strain NJN-6 could colonize the roots of banana plants after the application of BIO and produced active compounds which were beneficial for the growth of banana plants. PMID:23541032

  9. Poly(trimethylene carbonate-co-ε-caprolactone) promotes axonal growth.

    PubMed

    Rocha, Daniela Nogueira; Brites, Pedro; Fonseca, Carlos; Pêgo, Ana Paula

    2014-01-01

    Mammalian central nervous system (CNS) neurons do not regenerate after injury due to the inhibitory environment formed by the glial scar, largely constituted by myelin debris. The use of biomaterials to bridge the lesion area and the creation of an environment favoring axonal regeneration is an appealing approach, currently under investigation. This work aimed at assessing the suitability of three candidate polymers - poly(ε-caprolactone), poly(trimethylene carbonate-co-ε-caprolactone) (P(TMC-CL)) (11∶89 mol%) and poly(trimethylene carbonate) - with the final goal of using these materials in the development of conduits to promote spinal cord regeneration. Poly(L-lysine) (PLL) coated polymeric films were tested for neuronal cell adhesion and neurite outgrowth. At similar PLL film area coverage conditions, neuronal polarization and axonal elongation was significantly higher on P(TMC-CL) films. Furthermore, cortical neurons cultured on P(TMC-CL) were able to extend neurites even when seeded onto myelin. This effect was found to be mediated by the glycogen synthase kinase 3β (GSK3β) signaling pathway with impact on the collapsin response mediator protein 4 (CRMP4), suggesting that besides surface topography, nanomechanical properties were implicated in this process. The obtained results indicate P(TMC-CL) as a promising material for CNS regenerative applications as it promotes axonal growth, overcoming myelin inhibition. PMID:24586346

  10. TSPAN8 promotes gastric cancer growth and metastasis via ERK MAPK pathway

    PubMed Central

    Wei, Lunshou; Li, Yan; Suo, Zhimin

    2015-01-01

    Aims: This study was designed to investigate the effects of Tetraspanin 8 (TSPAN8) overexpression and TSPAN8 suppression on gastric cancer cell proliferation and invasion. Furthermore, whether extracellular-signal regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway was involved in TSPAN8’s function on gastric cancer cells was examined. Methods: The expression of TSPAN8 in human gastric cancer tissues and gastric cancer cell lines was detected using real-time PCR and western blot analysis. TSPAN8-pcDNA3.1 plasmid or TSPAN8 siRNA was transfected into the gastric cancer cell lines to overexpress or suppress TSPAN8. Cells were treated with U0126 to inhibit ERK MAPK pathway. Cell proliferation and invasion were assessed by MTT and transwell-matrigel assay. Results: TSPAN8 was overexpressed in human gastric cancer tissues and gastric cancer cell lines compared with the normal. TSPAN8 overexpression promoted cell proliferation and invasion, while TSPAN8 suppression inhibited cell proliferation and invasion. TSPAN8 could activate the ERK MAPK pathway in gastric cancer cells, and MEK-ERK inhibition reversed the effects of TSPAN8 overexpression on cell proliferation and invasion. Conclusion: This study firstly demonstrated that TSPAN8 promotes gastric cancer cell growth and metastasis at least partially through the activation of ERK MAPK pathway. These findings provided a novel molecular basis for the understanding and treatment of gastric cancer. PMID:26309511

  11. Poly(Trimethylene Carbonate-co-ε-Caprolactone) Promotes Axonal Growth

    PubMed Central

    Rocha, Daniela Nogueira; Brites, Pedro; Fonseca, Carlos; Pêgo, Ana Paula

    2014-01-01

    Mammalian central nervous system (CNS) neurons do not regenerate after injury due to the inhibitory environment formed by the glial scar, largely constituted by myelin debris. The use of biomaterials to bridge the lesion area and the creation of an environment favoring axonal regeneration is an appealing approach, currently under investigation. This work aimed at assessing the suitability of three candidate polymers – poly(ε-caprolactone), poly(trimethylene carbonate-co-ε-caprolactone) (P(TMC-CL)) (11∶89 mol%) and poly(trimethylene carbonate) - with the final goal of using these materials in the development of conduits to promote spinal cord regeneration. Poly(L-lysine) (PLL) coated polymeric films were tested for neuronal cell adhesion and neurite outgrowth. At similar PLL film area coverage conditions, neuronal polarization and axonal elongation was significantly higher on P(TMC-CL) films. Furthermore, cortical neurons cultured on P(TMC-CL) were able to extend neurites even when seeded onto myelin. This effect was found to be mediated by the glycogen synthase kinase 3β (GSK3β) signaling pathway with impact on the collapsin response mediator protein 4 (CRMP4), suggesting that besides surface topography, nanomechanical properties were implicated in this process. The obtained results indicate P(TMC-CL) as a promising material for CNS regenerative applications as it promotes axonal growth, overcoming myelin inhibition. PMID:24586346

  12. Prostaglandin F2α promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE

    PubMed Central

    Jansen, Katie M.; Pavlath, Grace K.

    2009-01-01

    During skeletal muscle growth and regeneration, the majority of differentiating myoblasts undergoes cell-cell fusion to form multinucleated myofibers, while a proportion of myoblasts undergoes apoptosis. The treatment of myoblasts with prostaglandin F2α (PGF2α) during myogenesis in vitro leads to the formation of large myotubes, but the mechanism by which PGF2α promotes myotube growth has not been investigated. Here, we demonstrate that PGF2α reduces cell death during myogenesis in vitro and in vivo. In addition, we show that PGF2α increases expression of the inhibitor of apoptosis protein (IAP) BRUCE through a pathway dependent upon the nuclear factor of activated T cell 2 (NFATC2) transcription factor. Importantly, PGF2α-mediated reduction in muscle cell death is dependent upon BRUCE, and overexpression of BRUCE is sufficient to promote muscle cell survival and growth. These results establish a previously unrecognized link between NFAT signaling and regulation of IAP expression and are the first to identify a signaling pathway that increases BRUCE expression. In addition, our results provide evidence that increasing the pool of muscle cells available for fusion by inhibiting cell death enhances myotube growth. PMID:18566603

  13. Peppermint Oil Promotes Hair Growth without Toxic Signs.

    PubMed

    Oh, Ji Young; Park, Min Ah; Kim, Young Chul

    2014-12-01

    Peppermint (Mentha piperita) is a plant native to Europe and has been widely used as a carminative and gastric stimulant worldwide. This plant also has been used in cosmetic formulations as a fragrance component and skin conditioning agent. This study investigated the effect of peppermint oil on hair growth in C57BL/6 mice. The animals were randomized into 4 groups based on different topical applications: saline (SA), jojoba oil (JO), 3% minoxidil (MXD), and 3% peppermint oil (PEO). The hair growth effects of the 4-week topical applications were evaluated in terms of hair growth, histological analysis, enzymatic activity of alkaline phosphatase (ALP), and gene expression of insulin-like growth factor-1 (IGF-1), known bio-markers for the enhanced hair growth. Of the 4 experimental groups, PEO group showed the most prominent hair growth effects; a significant increase in dermal thickness, follicle number, and follicle depth. ALP activity and IGF-1 expression also significantly increased in PEO group. Body weight gain and food efficiency were not significantly different between groups. These results suggest that PEO induces a rapid anagen stage and could be used for a practical agent for hair growth without change of body weight gain and food efficiency. PMID:25584150

  14. Hypoxia promotes drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling

    PubMed Central

    Zhao, Changfu; Zhang, Qiao; Yu, Tao; Sun, Shudong; Wang, Wenjun; Liu, Guangyao

    2016-01-01

    Purpose Drug resistance has been recognized to be a major obstacle to the chemotherapy for osteosarcoma. And the potential importance of hypoxia as a target to reverse drug resistance in osteosarcoma has been indicated, though the mechanism underlining such role is not clarified. The present study aims to investigate the role of hypoxia in the drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling. Experimental design We investigated the promotion of the resistance to doxorubicin of osteosarcoma MG-63 and U2-os cells in vitro, and then determined the role of hypoxia-inducible factor-1 (HIF-1)α and HIF-1β, the activation and regulatory role of AMPK in the osteosarcoma U2-os cells which were treated with doxorubicin under hypoxia. Results It was demonstrated that hypoxia significantly reduced the sensitivity of MG-63 and U2-os cells to doxorubicin, indicating an inhibited viability reduction and a reduced apoptosis promotion. And such reduced sensitivity was not associated with HIF-1α, though it was promoted by hypoxia in U2-os cells. Interestingly, the AMPK signaling was significantly promoted by hypoxia in the doxorubicin-treated U2-os cells, with a marked upregulation of phosphorylated AMPK (Thr 172) and phosphorylated acetyl-CoA carboxylase (ACC) (Ser 79), which were sensitive to the AMPK activator, AICAR and the AMPK inhibitor, Compound C. Moreover, the promoted AMPK activity by AICAR or the downregulated AMPK activity by Compound C significantly reduced or promoted the sensitivity of U2-os cells to doxorubicin. Conclusion The present study confirmed the AMPK signaling activation in the doxorubicin-treated osteosarcoma cells, in response to hypoxia, and the chemical upregulation or downregulation of AMPK signaling reduced or increased the chemo-sensitivity of osteosarcoma U2-os cells in vitro. Our study implies that AMPK inhibition might be a effective strategy to sensitize osteocarcoma cells to chemotherapy. PMID

  15. Phagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution.

    PubMed

    Luo, Bangwei; Wang, Jinsong; Liu, Zongwei; Shen, Zigang; Shi, Rongchen; Liu, Yu-Qi; Liu, Yu; Jiang, Man; Wu, Yuzhang; Zhang, Zhiren

    2016-01-01

    Inflammation resolution is an active process, the failure of which causes uncontrolled inflammation which underlies many chronic diseases. Therefore, endogenous pathways that regulate inflammation resolution are fundamental and of wide interest. Here, we demonstrate that phagocyte respiratory burst-induced hypoxia activates macrophage erythropoietin signalling to promote acute inflammation resolution. This signalling is activated following acute but not chronic inflammation. Pharmacological or genetical inhibition of the respiratory burst suppresses hypoxia and macrophage erythropoietin signalling. Macrophage-specific erythropoietin receptor-deficient mice and chronic granulomatous disease (CGD) mice, which lack the capacity for respiratory burst, display impaired inflammation resolution, and exogenous erythropoietin enhances this resolution in WT and CGD mice. Mechanistically, erythropoietin increases macrophage engulfment of apoptotic neutrophils via PPARγ, promotes macrophage removal of debris and enhances macrophage migration to draining lymph nodes. Together, our results provide evidences of an endogenous pathway that regulates inflammation resolution, with important implications for treating inflammatory conditions. PMID:27397585

  16. Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages.

    PubMed

    Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie; Wang, Yuzhen; Yu, Fang; Fan, Daping

    2016-08-01

    Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR. PMID:27196773

  17. Interception of host angiogenic signalling limits mycobacterial growth

    PubMed Central

    Oehlers, Stefan H.; Cronan, Mark R.; Scott, Ninecia R.; Thomas, Monica I.; Okuda, Kazuhide S.; Walton, Eric M.; Beerman, Rebecca W.; Crosier, Philip S.; Tobin, David M.

    2014-01-01

    Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis1,2. Here we examine the development and consequences of vascularisation of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model characterised by organised granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis2. Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule VEGFA. Pharmacological inhibition of the VEGF pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergise with the first-line anti-tubercular antibiotic rifampicin as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations3. Our data suggest that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting TB therapy, particularly in extensively drug-resistant disease where current antibiotic regimens are largely ineffective. PMID:25470057

  18. Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

    SciTech Connect

    Hayata, Nozomi; Fujio, Yasushi; Yamamoto, Yasuhiro; Iwakura, Tomohiko; Obana, Masanori; Takai, Mika; Mohri, Tomomi; Nonen, Shinpei; Maeda, Makiko; Azuma, Junichi

    2008-05-30

    In the process of cardiac remodeling, connective tissue growth factor (CTGF/CCN2) is secreted from cardiac myocytes. Though CTGF is well known to promote fibroblast proliferation, its pathophysiological effects in cardiac myocytes remain to be elucidated. In this study, we examined the biological effects of CTGF in rat neonatal cardiomyocytes. Cardiac myocytes stimulated with full length CTGF and its C-terminal region peptide showed the increase in cell surface area. Similar to hypertrophic ligands for G-protein coupled receptors, such as endothelin-1, CTGF activated amino acid uptake; however, CTGF-induced hypertrophy is not associated with the increased expression of skeletal actin or BNP, analyzed by Northern-blotting. CTGF treatment activated ERK1/2, p38 MAPK, JNK and Akt. The inhibition of Akt by transducing dominant-negative Akt abrogated CTGF-mediated increase in cell size, while the inhibition of MAP kinases did not affect the cardiac hypertrophy. These findings indicate that CTGF is a novel hypertrophic factor in cardiac myocytes.

  19. Evaluation of Phytase Producing Bacteria for Their Plant Growth Promoting Activities

    PubMed Central

    Singh, Prashant; Agrawal, Sanjeev

    2014-01-01

    Bacterial inoculants are known to possess plant growth promoting abilities and have potential as liquid biofertilizer application. Four phytase producing bacterial isolates (phytase activity in the range of 0.076–0.174 U/mL), identified as Advenella species (PB-05, PB-06, and PB-10) and Cellulosimicrobium sp. PB-09, were analyzed for their plant growth promoting activities like siderophore production, IAA production, HCN production, ammonia production, phosphate solubilization, and antifungal activity. All isolates were positive for the above characteristics except for HCN production. The solubilization index for phosphorus on Pikovskaya agar plates was in the range of 2–4. Significant amount of IAA (7.19 to 35.03 μg/mL) production and solubilized phosphate (189.53 to 746.84 μg/mL) was noticed by these isolates at different time intervals. Besides that, a greenhouse study was also conducted with Indian mustard to evaluate the potential of these isolates to promote plant growth. Effect of seed bacterization on various plant growth parameters and P uptake by plant were used as indicators. The plant growth promoting ability of bacterial isolates in pot experiments was correlated to IAA production, phosphate solubilization, and other in vitro tests. On the basis of present findings, isolate PB-06 was most promising in plant growth promotion with multiple growth promoting characteristics. PMID:24669222

  20. Positive and negative tissue-specific signaling by a nematode epidermal growth factor receptor.

    PubMed Central

    Lesa, G M; Sternberg, P W

    1997-01-01

    The major determinants of receptor tissue tyrosine kinase (RTK) signaling specificity have been proposed to be Src homology 2 (SH2) binding sites, phosphotyrosine-containing oligopeptides in the cytoplasmic domain of the receptor. The Caenorhabditis elegans epidermal growth factor receptor homologue LET-23 has multiple functions during development and has eight potential SH2-binding sites in a region carboxyl terminal to its kinase domain. By analyzing transgenic nematodes for three distinct LET-23 functions, we show that six of eight potential sites function in vivo and that they are required for most, but not all, of LET-23 activity. A single site is necessary and sufficient to promote wild-type fertility. Three other sites activate the RAS pathway and are involved only in viability and vulval differentiation. A fifth site is promiscuous and can mediate all three LET-23 functions. An additional site mediates tissue-specific negative regulation. Putative SH2 binding sites are thus key effectors of both cell-specific and negative regulation in an intact organism. We suggest two distinct mechanisms for tissue-specific RTK-mediated signaling. A positive mechanism would promote RTK function through effectors present only in certain cell types. A negative mechanism would inhibit RTK function through tissue-specific negative regulators. Images PMID:9168466

  1. Clinical significance of nerve growth factor and tropomyosin-receptor-kinase signaling pathway in intrahepatic cholangiocarcinoma

    PubMed Central

    Yang, Xiao-Qing; Xu, Yun-Fei; Guo, Sen; Liu, Yi; Ning, Shang-Lei; Lu, Xiao-Fei; Yang, Hui; Chen, Yu-Xin

    2014-01-01

    AIM: To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase (NGF-TrkA) signaling pathway and prognosis in intrahepatic cholangiocarcinoma (IHCC). METHODS: NGF and TrkA expression in 83 samples of IHCC was assessed by immunohistochemistry. Correlations between NGF-TrkA expression and clinicopathological features were analyzed by χ2 test. Moreover, we evaluated the association between NGF-TrkA and overall survival by univariate and multivariate analysis. With experiments in vitro, we investigated the crucial role of NGF-TrkA on proliferation and invasion of IHCC cells with recombinant NGF-β stimulation. RESULTS: We found that NGF and TrkA expression was significantly related with differentiation (P = 0.024) and intraneural invasion (P = 0.003), respectively. Additionally, double higher expression of NGF and TrkA was identified as an independent prognostic factor in IHCC (P = 0.003). Moreover, we demonstrated that NGF-TrkA signaling pathway can promote IHCC proliferation and invasion. CONCLUSION: NGF-TrkA double higher expression is an independent prognostic factor in IHCC. NGF-TrkA pathway can promote IHCC progression, indicating that NGF-TrkA may become a potential drug target. PMID:24744599

  2. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy

    PubMed Central

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  3. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy.

    PubMed

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  4. Thymidine Phosphorylase is Angiogenic and Promotes Tumor Growth

    NASA Astrophysics Data System (ADS)

    Moghaddam, Amir; Zhang, Hua-Tang; Fan, Tai-Ping D.; Hu, De-En; Lees, Vivien C.; Turley, Helen; Fox, Stephen B.; Gatter, Kevin C.; Harris, Adrian L.; Bicknell, Roy

    1995-02-01

    Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). The effect of TP on [methyl-^3H]thymidine uptake does not arise from de novo DNA synthesis and the molecule is not a growth factor. Despite this, TP is strongly angiogenic in a rat sponge and freeze-injured skin graft model. Neutralizing antibodies and site-directed mutagenesis confirmed that the enzyme activity of TP is a condition for its angiogenic activity. The level of TP was found to be elevated in human breast tumors compared to normal breast tissue (P < 0.001). Overexpression of TP in MCF-7 breast carcinoma cells had no effect on growth in vitro but markedly enhanced tumor growth in vivo. These data and the correlation of expression in tumors with malignancy identify TP as a target for antitumor strategies.

  5. The Protein Elicitor PevD1 Enhances Resistance to Pathogens and Promotes Growth in Arabidopsis

    PubMed Central

    Liu, Mengjie; Khan, Najeeb Ullah; Wang, Ningbo; Yang, Xiufen; Qiu, Dewen

    2016-01-01

    The protein elicitor PevD1, isolated from Verticillium dahlia, could enhance resistance to TMV in tobacco and Verticillium wilt in cotton. Here, the pevd1 gene was over-expressed in wild type (WT) Arabidopsis, and its biological functions were investigated. Our results showed that the transgenic lines were more resistant to Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000 than the WT line was. In transgenic plants, both the germination time and bolting time required were significantly shorter and fresh weights and plant heights were significantly higher than those in the WT line. A transcriptomics study using digital gene expression profiling (DGE) was performed in transgenic and WT Arabidopsis. One hundred and thirty-six differentially expressed genes were identified. In transgenic Arabidopsis, three critical regulators of JA biosynthesis were up-regulated and JA levels were slightly increased. Three important repressors of the ABA-responsive pathway were up-regulated, indicating that ABA signal transduction may be suppressed. One CML and two WRKY TFs involved in Ca2+-responsive pathways were up-regulated, indicating that this pathway may have been triggered. In conclusion, we show that PevD1 is involved in regulating several plant endogenous signal transduction pathways and regulatory networks to enhance resistance and promote growth and development in Arabidopsis. PMID:27489497

  6. The Protein Elicitor PevD1 Enhances Resistance to Pathogens and Promotes Growth in Arabidopsis.

    PubMed

    Liu, Mengjie; Khan, Najeeb Ullah; Wang, Ningbo; Yang, Xiufen; Qiu, Dewen

    2016-01-01

    The protein elicitor PevD1, isolated from Verticillium dahlia, could enhance resistance to TMV in tobacco and Verticillium wilt in cotton. Here, the pevd1 gene was over-expressed in wild type (WT) Arabidopsis, and its biological functions were investigated. Our results showed that the transgenic lines were more resistant to Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000 than the WT line was. In transgenic plants, both the germination time and bolting time required were significantly shorter and fresh weights and plant heights were significantly higher than those in the WT line. A transcriptomics study using digital gene expression profiling (DGE) was performed in transgenic and WT Arabidopsis. One hundred and thirty-six differentially expressed genes were identified. In transgenic Arabidopsis, three critical regulators of JA biosynthesis were up-regulated and JA levels were slightly increased. Three important repressors of the ABA-responsive pathway were up-regulated, indicating that ABA signal transduction may be suppressed. One CML and two WRKY TFs involved in Ca(2+)-responsive pathways were up-regulated, indicating that this pathway may have been triggered. In conclusion, we show that PevD1 is involved in regulating several plant endogenous signal transduction pathways and regulatory networks to enhance resistance and promote growth and development in Arabidopsis. PMID:27489497

  7. Promoters maintain their relative activity levels under different growth conditions

    PubMed Central

    Keren, Leeat; Zackay, Ora; Lotan-Pompan, Maya; Barenholz, Uri; Dekel, Erez; Sasson, Vered; Aidelberg, Guy; Bren, Anat; Zeevi, Danny; Weinberger, Adina; Alon, Uri; Milo, Ron; Segal, Eran

    2013-01-01

    Most genes change expression levels across conditions, but it is unclear which of these changes represents specific regulation and what determines their quantitative degree. Here, we accurately measured activities of ∼900 S. cerevisiae and ∼1800 E. coli promoters using fluorescent reporters. We show that in both organisms 60–90% of promoters change their expression between conditions by a constant global scaling factor that depends only on the conditions and not on the promoter's identity. Quantifying such global effects allows precise characterization of specific regulation—promoters deviating from the global scale line. These are organized into few functionally related groups that also adhere to scale lines and preserve their relative activities across conditions. Thus, only several scaling factors suffice to accurately describe genome-wide expression profiles across conditions. We present a parameter-free passive resource allocation model that quantitatively accounts for the global scaling factors. It suggests that many changes in expression across conditions result from global effects and not specific regulation, and provides means for quantitative interpretation of expression profiles. PMID:24169404

  8. Promoters maintain their relative activity levels under different growth conditions.

    PubMed

    Keren, Leeat; Zackay, Ora; Lotan-Pompan, Maya; Barenholz, Uri; Dekel, Erez; Sasson, Vered; Aidelberg, Guy; Bren, Anat; Zeevi, Danny; Weinberger, Adina; Alon, Uri; Milo, Ron; Segal, Eran

    2013-01-01

    Most genes change expression levels across conditions, but it is unclear which of these changes represents specific regulation and what determines their quantitative degree. Here, we accurately measured activities of ~900 S. cerevisiae and ~1800 E. coli promoters using fluorescent reporters. We show that in both organisms 60-90% of promoters change their expression between conditions by a constant global scaling factor that depends only on the conditions and not on the promoter's identity. Quantifying such global effects allows precise characterization of specific regulation-promoters deviating from the global scale line. These are organized into few functionally related groups that also adhere to scale lines and preserve their relative activities across conditions. Thus, only several scaling factors suffice to accurately describe genome-wide expression profiles across conditions. We present a parameter-free passive resource allocation model that quantitatively accounts for the global scaling factors. It suggests that many changes in expression across conditions result from global effects and not specific regulation, and provides means for quantitative interpretation of expression profiles. PMID:24169404

  9. Endothelial Cords Promote Tumor Initial Growth prior to Vascular Function through a Paracrine Mechanism

    PubMed Central

    Zhao, Chengjian; Zhang, Wei; Zhao, Yuwei; Yang, Yun; Luo, Hui; Ji, Gaili; Dong, E; Deng, Hongxing; Lin, Shuo; Wei, Yuquan; Yang, Hanshuo

    2016-01-01

    The angiogenic switch is an important oncogenic step that determines whether microtumors remain dormant or progresses further. It has been generally perceived that the primary function of this tumorgenic event is to supply oxygen and nutrients through blood circulation. Using in vivo imaging of zebrafish and mouse tumor models, we showed that endothelial cords aggressively penetrated into microtumors and remained non-circulatory for several days before undergoing vascular blood perfusion. Unexpectedly, we found that initial tumor growth in both models was significantly reduced if endothelial cords were removed by blocking VEGF-VEGFR2 signaling or using a vascular deficient zebrafish mutant. It was further shown that soluble factors including IL-8, secreted by endothelial cells (ECs) were responsible for stimulating tumor cells proliferation. These findings establish that tumor angiogenesis play a much earlier and broader role in promoting tumor growth, which is independent of vascular circulation. Understanding this novel mechanism of angiogenic tumor progression offers new entry points for cancer therapeutics. PMID:26762853

  10. Estrogen Receptor Alpha (ERα)-Associated Fibroblasts Promote Cell Growth in Prostate Cancer.

    PubMed

    Da, Jun; Lu, Mujun; Wang, Zhong

    2015-12-01

    Estrogen receptor (ER) is expressed in cancer-associated fibroblasts (CAFs) in the stromal compartment of cancerous prostate. However, the effect of ERα in CAF cells on prostate cancer (PCa) cell growth remains unclear. We used lentiviral transduction to stably express ERα in CAF cells isolated from transgenic adenocarcinoma of the mouse prostate model. MTT and 3D colony-formation assays demonstrated that conditioned medium from ERα-expressing CAF cells (CAF-ERα+) promoted cell proliferation and colony growth of various PCa cell lines, such as PC3, LNCaP, 22RV1, and C4-2. We further confirmed the in vitro data by orthotopically co-implanting 22RV1, transfected with firefly luciferase, and CAF-ERα+ cells in vivo using mouse model. Mice co-implanted with CAF-ERα+ exhibited stronger luciferase signals and bigger tumor size compared to animals co-implanted with CAF that do not express ER. Our results demonstrate that ER expressed in CAF might play a pro-proliferative role in PCa. PMID:27259327

  11. TP508 accelerates fracture repair by promoting cell growth over cell death

    SciTech Connect

    Li Xinmin; Wang Hali; Touma, Edward; Qi Yuchen; Rousseau, Emma; Quigg, Richard J.; Ryaby, James T.

    2007-12-07

    TP508 is a synthetic 23-amino acid peptide representing a receptor-binding domain of human thrombin. We have previously shown that a single injection of TP508 accelerates fracture healing in a rat femoral fracture model. To understand how TP508 acts at the protein level during fracture healing, we compared the translational profiles between saline-control and fractured femur at six time points after TP508 treatment using the second generation of BD Clontech{sup TM} Antibody Microarray. Here, we demonstrate that TP508 accelerates fracture healing by modulating expression levels of proteins primarily involved in the functional categories of cell cycle, cellular growth and proliferation, and cell death. The majority of those proteins are physically interrelated and functionally overlapped. The action of those proteins is highlighted by a central theme of promoting cell growth via balance of cell survival over cell death signals. This appears to occur through the stimulation of several bone healing pathways including cell cycle-G1/S checkpoint regulation, apoptosis, JAK/STAT, NF-{kappa}B, PDGF, PI3K/AKT, PTEN, and ERK/MAPK.

  12. Lewisy Promotes Migration of Oral Cancer Cells by Glycosylation of Epidermal Growth Factor Receptor

    PubMed Central

    Lin, Wei-Ling; Lin, Yi-Shiuan; Shi, Guey-Yueh; Chang, Chuan-Fa; Wu, Hua-Lin

    2015-01-01

    Aberrant glycosylation changes normal cellular functions and represents a specific hallmark of cancer. Lewisy (Ley) carbohydrate upregulation has been reported in a variety of cancers, including oral squamous cell carcinoma (OSCC). A high level of Ley expression is related to poor prognosis of patients with oral cancer. However, it is unclear how Ley mediates oral cancer progression. In this study, the role of Ley in OSCC was explored. Our data showed that Ley was upregulated in HSC-3 and OC-2 OSCC cell lines. Particularly, glycosylation of epidermal growth factor receptor (EGFR) with Ley was found in OC-2 cells, and this modification was absent upon inhibition of Ley synthesis. The absence of Ley glycosylation of EGFR weakened phosphorylation of AKT and ERK in response to epidermal growth factor (EGF). Additionally, EGF-triggered cell migration was reduced, but cell proliferation was not affected. Ley modification stabilized EGFR upon ligand activation. Conversely, absence of Ley glycosylation accelerated EGFR degradation. In summary, these results indicate that increased expression of Ley in OSCC cells is able to promote cell migration by modifying EGFR which in turn stabilizes EGFR expression and downstream signaling. Targeting Ley on EGFR could have a potential therapeutic effect on oral cancer. PMID:25799278

  13. Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance

    PubMed Central

    Javidi-Sharifi, Nathalie; Traer, Elie; Martinez, Jacqueline; Gupta, Anu; Taguchi, Takehiro; Dunlap, Jennifer; Heinrich, Michael C.; Corless, Christopher L.; Rubin, Brian P.; Druker, Brian J.; Tyner, Jeffrey W.

    2014-01-01

    Kinase inhibitors such as imatinib have dramatically improved outcomes for GIST patients, but many patients develop resistance to these treatments. While in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients development resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an immunohistochemical analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend towards increased expression in imatinib-naïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multi-kinase inhibitors that target FGFR3 as promising strategies to improve treatment of GIST patients with de novo or acquired resistance to imatinib. PMID:25432174

  14. Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance.

    PubMed

    Javidi-Sharifi, Nathalie; Traer, Elie; Martinez, Jacqueline; Gupta, Anu; Taguchi, Takehiro; Dunlap, Jennifer; Heinrich, Michael C; Corless, Christopher L; Rubin, Brian P; Druker, Brian J; Tyner, Jeffrey W

    2015-03-01

    Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinib-naïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib. PMID:25432174

  15. The Bro1-Domain Protein, EGO-2, Promotes Notch Signaling in Caenorhabditis elegans

    PubMed Central

    Liu, Ying; Maine, Eleanor M.

    2007-01-01

    In Caenorhabditis elegans, as in other animals, Notch-type signaling mediates numerous inductive events during development. The mechanism of Notch-type signaling involves proteolytic cleavage of the receptor and subsequent transport of the receptor intracellular domain to the nucleus, where it acts as a transcriptional regulator. Notch-type signaling activity is modulated by post-translational modifications and endocytosis of ligand and receptor. We previously identified the ego-2 (enhancer of glp-1) gene as a positive regulator of germline proliferation that interacts genetically with the GLP-1/Notch signaling pathway in the germline. Here, we show that ego-2 positively regulates signaling in various tissues via both GLP-1 and the second C. elegans Notch-type receptor, LIN-12. ego-2 activity also promotes aspects of development not known to require GLP-1 or LIN-12. The EGO-2 protein contains a Bro1 domain, which is known in other systems to localize to certain endosomal compartments. EGO-2 activity in the soma promotes GLP-1 signaling in the germline, consistent with a role for EGO-2 in production of active ligand. Another C. elegans Bro1-domain protein, ALX-1, is known to interact physically with LIN-12/Notch. We document a complex phenotypic interaction between ego-2 and alx-1, consistent with their relationship being antagonistic with respect to some developmental processes and agonistic with respect to others. PMID:17603118

  16. Transforming growth factor-beta during carcinogenesis: the shift from epithelial to mesenchymal signaling.

    PubMed

    Matsuzaki, Koichi; Okazaki, Kazuichi

    2006-04-01

    Transforming growth factor-beta (TGF-beta) activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), changing unphosphorylated Smad3 to its phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). While the TbetaRI/pSmad3C pathway inhibits growth of normal epithelial cells, JNK/pSmad3L-mediated signaling is involved in invasion by activated mesenchymal cells. During sporadic human colorectal carcinogenesis, TGF-beta signaling confers a selective advantage on tumor cells by shifting from the TbetaRI/pSmad3C pathway characteristic of mature epithelial cells to the JNK/pSmad3L pathway, which is more characteristic of the state of flux shown by the activated mesenchymal cells. JNK acts as a regulator of TGF-beta signaling by increasing the basal level of pSmad3L available for action in the nuclei of the invasive adenocarcinoma, in the meantime shutting down TGF-beta-dependent nuclear activity of pSmad3C. Loss of epithelial homeostasis and acquisition of a migratory, mesenchymal phenotype are essential for tumor invasion. From the viewpoint of TGF-beta signaling, a key therapeutic aim in cancer would be restoration of the lost tumor suppressor function observed in normal colorectal epithelial cells at the expense of effects promoting aggressive behavior of the adenocarcinoma. Specific inhibitors of the JNK/pSmad3L pathway might prove useful in this respect. In the case of molecularly targeted therapy for human cancer, pSmad3L and pSmad3C could be assessed as biomarkers to evaluate the likely benefit from specific inhibition of the JNK/pSmad3L pathway. PMID:16741607

  17. Effect of plant growth-promoting bacteria on the growth and fructan production of Agave americana L.

    PubMed

    De La Torre-Ruiz, Neyser; Ruiz-Valdiviezo, Víctor Manuel; Rincón-Molina, Clara Ivette; Rodríguez-Mendiola, Martha; Arias-Castro, Carlos; Gutiérrez-Miceli, Federico Antonio; Palomeque-Dominguez, Héctor; Rincón-Rosales, Reiner

    2016-01-01

    The effect of plant growth-promoting bacteria inoculation on plant growth and the sugar content in Agave americana was assessed. The bacterial strains ACO-34A, ACO-40, and ACO-140, isolated from the A. americana rhizosphere, were selected for this study to evaluate their phenotypic and genotypic characteristics. The three bacterial strains were evaluated via plant inoculation assays, and Azospirillum brasilense Cd served as a control strain. Phylogenetic analysis based on the 16S rRNA gene showed that strains ACO-34A, ACO-40 and ACO-140 were Rhizobium daejeonense, Acinetobacter calcoaceticus and Pseudomonas mosselii, respectively. All of the strains were able to synthesize indole-3-acetic acid (IAA), solubilize phosphate, and had nitrogenase activity. Inoculation using the plant growth-promoting bacteria strains had a significant effect (p<0.05) on plant growth and the sugar content of A. americana, showing that these native plant growth-promoting bacteria are a practical, simple, and efficient alternative to promote the growth of agave plants with proper biological characteristics for agroindustrial and biotechnological use and to increase the sugar content in this agave species. PMID:27268113

  18. Draft Genome Sequence of Plant Growth-Promoting Rhizobacterium Pantoea sp. Strain AS-PWVM4

    PubMed Central

    Khatri, Indu; Kaur, Sukhvir; Devi, Usha; Kumar, Navinder; Sharma, Deepak

    2013-01-01

    Nonpathogenic Pantoea spp. have been shown to confer biofertilizer and biocontrol activities, indicating their potential for increasing crop yield. Herein, we provide the high-quality genome sequence of Pantoea sp. strain AS-PWVM4, a Gram-negative motile plant growth-promoting rhizobacterium isolated from a pomegranate plant. The 4.9-Mb genome contains genes related to plant growth promotion and the synthesis of siderophores. PMID:24309733

  19. Targeted blockade of JAK/STAT3 signaling inhibits ovarian carcinoma growth

    PubMed Central

    Gritsina, Galina; Xiao, Fang; O'Brien, Shane W.; Gabbasov, Rashid; Maglaty, Marisa A.; Xu, Ren-Huan; Thapa, Roshan J.; Zhou, Yan; Nicolas, Emmanuelle; Litwin, Samuel; Balachandran, Siddharth; Sigal, Luis J.; Huszar, Dennis; Connolly, Denise C.

    2015-01-01

    Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. PMID:25646015

  20. Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of STAT3 signaling pathway.

    PubMed

    Cai, Qiaoyan; Lin, Jiumao; Wei, Lihui; Zhang, Ling; Wang, Lili; Zhan, Youzhi; Zeng, Jianwei; Xu, Wei; Shen, Aling; Hong, Zhenfeng; Peng, Jun

    2012-01-01

    Signal Transducer and Activator of Transcription 3 (STAT3), a common oncogenic mediator, is constitutively activated in many types of human cancers; therefore it is a major focus in the development of novel anti-cancer agents. Hedyotis diffusa Willd has been used as a major component in several Chinese medicine formulas for the clinical treatment of colorectal cancer (CRC). However, the precise mechanism of its anti-tumor activity remains largely unclear. Using a CRC mouse xenograft model, in the present study we evaluated the effect of the ethanol extract of Hedyotis diffusa Willd (EEHDW) on tumor growth in vivo and investigated the underlying molecular mechanisms. We found that EEHDW reduced tumor volume and tumor weight, but had no effect on body weight gain in CRC mice, demonstrating that EEHDW can inhibit CRC growth in vivo without apparent adverse effect. In addition, EEHDW treatment suppressed STAT3 phosphorylation in tumor tissues, which in turn resulted in the promotion of cancer cell apoptosis and inhibition of proliferation. Moreover, EEHDW treatment altered the expression pattern of several important target genes of the STAT3 signaling pathway, i.e., decreased expression of Cyclin D1, CDK4 and Bcl-2 as well as up-regulated p21 and Bax. These results suggest that suppression of the STAT3 pathway might be one of the mechanisms by which EEHDW treats colorectal cancer. PMID:22754353

  1. Influence of promoter and signal peptide on the expression of pullulanase in Bacillus subtilis.

    PubMed

    Wang, Yapin; Liu, Yihan; Wang, Zhengxiang; Lu, Fuping

    2014-09-01

    To achieve efficient expression and secretion of a biologically-active pullulanase, the effect of promoter and signal peptide on the production of pullulanase was studied. Three types of promoters (PP43, P apr and P amy ) and four types of signal peptides (SP sacB , SP amy , SP aprl and SP aprs ) were combined to construct twelve expression cassettes for pullulanase in Bacillus subtilis. The pullulanase activity assay was employed to quantify the level of differential expression, and a real-time PCR assay was applied to comparatively track the transcriptional level. Under the same experimental conditions, the potency ratios among the three promoters were P apr  > P amy  > PP43. The secretion efficiency ratios mediated by the signal peptides were SP sacB  > SP amy  > SP aprs  > SP aprl . The highest yield of pullulanase could be achieved under the promotion mediated by P apr and secretion by SP sacB . PMID:24793495

  2. Neuropilin-2 promotes melanoma growth and progression in vivo.

    PubMed

    Moriarty, Whei F; Kim, Edward; Gerber, Stephanie A; Hammers, Hans; Alani, Rhoda M

    2016-08-01

    Tumor cell interactions with their microenvironment, and neighboring endothelial cells in particular, are critical for tumor cell survival and the metastatic process. Within the spectrum of tumors, melanomas are notorious for their ability to metastasize at a relatively early stage of development; however, little is known about the molecular pathways mediating this process. We recently performed a screen to assess critical mediators of melanoma metastasis by evaluating melanoma-endothelial cell communication. Neuropilin-2 (NRP2), a cell surface receptor involved in angiogenesis and axonal guidance, was found to be an important mediator of melanoma-endothelial cell cross-talk in these studies. Here we seek to further define the role of NRP2 in melanoma growth and progression. We use stable gene silencing of NRP2 in melanomas from varying stages of tumor progression to define the role of NRP2 in melanoma growth, migration, invasion, and metastasis. We found that NRP2 gene silencing in metastatic melanoma cell lines inhibited tumor cell growth in vitro; furthermore, knockdown of NRP2 expression in the metastatic melanoma cell line 1205Lu significantly inhibited in-vivo tumor growth and metastasis. We conclude that NRP2 plays an important role in mediating melanoma growth and metastasis and suggest that targeting this cell surface molecule may represent a significant therapeutic strategy for patients diagnosed with aggressive forms of melanoma. PMID:26881875

  3. Making Just Tenure and Promotion Decisions Using the Objective Knowledge Growth Framework

    ERIC Educational Resources Information Center

    Chitpin, Stephanie

    2015-01-01

    Purpose: The purpose of this paper is to utilize the Objective Knowledge Growth Framework (OKGF) to promote a better understanding of the evaluating tenure and promotion processes. Design/Methodology/Approach: A scenario is created to illustrate the concept of using OKGF. Findings: The framework aims to support decision makers in identifying the…

  4. Different Growth Promoting Effects of Endophytic Bacteria on Invasive and Native Clonal Plants

    PubMed Central

    Dai, Zhi-Cong; Fu, Wei; Wan, Ling-Yun; Cai, Hong-Hong; Wang, Ning; Qi, Shan-Shan; Du, Dao-Lin

    2016-01-01

    The role of the interactions between endophytes and alien plants has been unclear yet in plant invasion. We used a completely germ-free culture system to quantify the plant growth-promoting (PGP) effects of endophytic bacteria Bacillus sp. on aseptic seedlings of Wedelia trilobata and of its native clonal congener W. chinensis. The endophytic bacteria did not affect the growth of W. chinensis, but they significantly promoted the growth of W. trilobata. With the PGP effects of endophytic bacteria, relative change ratios of the clonal traits and the ramets’ growth traits of W. trilobata were significantly greater than those of W. chinensis. Our results indicate that the growth-promoting effects of endophytes may differ between invasive and native clonal plants, and the endophytes of invasive plant may be host-specific to facilitate plant invasion. PMID:27252722

  5. Different Growth Promoting Effects of Endophytic Bacteria on Invasive and Native Clonal Plants.

    PubMed

    Dai, Zhi-Cong; Fu, Wei; Wan, Ling-Yun; Cai, Hong-Hong; Wang, Ning; Qi, Shan-Shan; Du, Dao-Lin

    2016-01-01

    The role of the interactions between endophytes and alien plants has been unclear yet in plant invasion. We used a completely germ-free culture system to quantify the plant growth-promoting (PGP) effects of endophytic bacteria Bacillus sp. on aseptic seedlings of Wedelia trilobata and of its native clonal congener W. chinensis. The endophytic bacteria did not affect the growth of W. chinensis, but they significantly promoted the growth of W. trilobata. With the PGP effects of endophytic bacteria, relative change ratios of the clonal traits and the ramets' growth traits of W. trilobata were significantly greater than those of W. chinensis. Our results indicate that the growth-promoting effects of endophytes may differ between invasive and native clonal plants, and the endophytes of invasive plant may be host-specific to facilitate plant invasion. PMID:27252722

  6. Biodiversity Promotes Tree Growth during Succession in Subtropical Forest

    PubMed Central

    Barrufol, Martin; Schmid, Bernhard; Bruelheide, Helge; Chi, Xiulian; Hector, Andrew; Ma, Keping; Michalski, Stefan; Tang, Zhiyao; Niklaus, Pascal A.

    2013-01-01

    Losses of plant species diversity can affect ecosystem functioning, with decreased primary productivity being the most frequently reported effect in experimental plant assemblages, including tree plantations. Less is known about the role of biodiversity in natural ecosystems, including forests, despite their importance for global biogeochemical cycling and climate. In general, experimental manipulations of tree diversity will take decades to yield final results. To date, biodiversity effects in natural forests therefore have only been reported from sample surveys or meta-analyses with plots not initially selected for diversity. We studied biomass and growth of subtropical forests stands in southeastern China. Taking advantage of variation in species recruitment during secondary succession, we adopted a comparative study design selecting forest plots to span a gradient in species richness. We repeatedly censored the stem diameter of two tree size cohorts, comprising 93 species belonging to 57 genera and 33 families. Tree size and growth were analyzed in dependence of species richness, the functional diversity of growth-related traits, and phylogenetic diversity, using both general linear and structural equation modeling. Successional age covaried with diversity, but differently so in the two size cohorts. Plot-level stem basal area and growth were positively related with species richness, while growth was negatively related to successional age. The productivity increase in species-rich, functionally and phylogenetically diverse plots was driven by both larger mean sizes and larger numbers of trees. The biodiversity effects we report exceed those from experimental studies, sample surveys and meta-analyses, suggesting that subtropical tree diversity is an important driver of forest productivity and re-growth after disturbance that supports the provision of ecological services by these ecosystems. PMID:24303037

  7. Biodiversity promotes tree growth during succession in subtropical forest.

    PubMed

    Barrufol, Martin; Schmid, Bernhard; Bruelheide, Helge; Chi, Xiulian; Hector, Andrew; Ma, Keping; Michalski, Stefan; Tang, Zhiyao; Niklaus, Pascal A

    2013-01-01

    Losses of plant species diversity can affect ecosystem functioning, with decreased primary productivity being the most frequently reported effect in experimental plant assemblages, including tree plantations. Less is known about the role of biodiversity in natural ecosystems, including forests, despite their importance for global biogeochemical cycling and climate. In general, experimental manipulations of tree diversity will take decades to yield final results. To date, biodiversity effects in natural forests therefore have only been reported from sample surveys or meta-analyses with plots not initially selected for diversity. We studied biomass and growth of subtropical forests stands in southeastern China. Taking advantage of variation in species recruitment during secondary succession, we adopted a comparative study design selecting forest plots to span a gradient in species richness. We repeatedly censored the stem diameter of two tree size cohorts, comprising 93 species belonging to 57 genera and 33 families. Tree size and growth were analyzed in dependence of species richness, the functional diversity of growth-related traits, and phylogenetic diversity, using both general linear and structural equation modeling. Successional age covaried with diversity, but differently so in the two size cohorts. Plot-level stem basal area and growth were positively related with species richness, while growth was negatively related to successional age. The productivity increase in species-rich, functionally and phylogenetically diverse plots was driven by both larger mean sizes and larger numbers of trees. The biodiversity effects we report exceed those from experimental studies, sample surveys and meta-analyses, suggesting that subtropical tree diversity is an important driver of forest productivity and re-growth after disturbance that supports the provision of ecological services by these ecosystems. PMID:24303037

  8. Cellular response to micropatterned growth promoting and inhibitory substrates

    PubMed Central

    2013-01-01

    Background Normal development and the response to injury both require cell growth, migration and morphological remodeling, guided by a complex local landscape of permissive and inhibitory cues. A standard approach for studying by such cues is to culture cells on uniform substrates containing known concentrations of these molecules, however this method fails to represent the molecular complexity of the natural growth environment. Results To mimic the local complexity of environmental conditions in vitro, we used a contact micropatterning technique to examine cell growth and differentiation on patterned substrates printed with the commonly studied growth permissive and inhibitory substrates, poly-L-lysine (PLL) and myelin, respectively. We show that micropatterning of PLL can be used to direct adherence and axonal outgrowth of hippocampal and cortical neurons as well as other cells with diverse morphologies like Oli-neu oligodendrocyte progenitor cell lines and fibroblast-like COS7 cells in culture. Surprisingly, COS7 cells exhibited a preference for low concentration (1 pg/mL) PLL zones over adjacent zones printed with high concentrations (1 mg/mL). We demonstrate that micropatterning is also useful for studying factors that inhibit growth as it can direct cells to grow along straight lines that are easy to quantify. Furthermore, we provide the first demonstration of microcontact printing of myelin-associated proteins and show that they impair process outgrowth from Oli-neu oligodendrocyte precursor cells. Conclusion We conclude that microcontact printing is an efficient and reproducible method for patterning proteins and brain-derived myelin on glass surfaces in order to study the effects of the microenvironment on cell growth and morphogenesis. PMID:24119185

  9. MEK1 signaling promotes self-renewal and tumorigenicity of liver cancer stem cells via maintaining SIRT1 protein stabilization

    PubMed Central

    Cheng, Jiamin; Liu, Chungang; Liu, Limei; Chen, Xuejiao; Shan, Juanjuan; Shen, Junjie; Zhu, Wei; Qian, Cheng

    2016-01-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. This high mortality has been commonly attributed to the presence of residual cancer stem cells (CSCs). Meanwhile, MEK1 signaling is regarded as a key molecular in HCC maintenance and development. However, nobody has figured out the particular mechanisms that how MEK1 signaling regulates liver CSCs self-renewal. In this study, we show that inhibition or depletion of MEK1 can significantly decrease liver CSCs self-renewal and tumor growth both in vitro and vivo conditions. Furthermore, we demonstrate that MEK1 signaling promotes liver CSCs self-renewal and tumorigenicity by maintaining SIRT1 level. Mechanistically, MEK1 signaling keeps SIRT1 protein stabilization through activating SIRT1 ubiquitination, which inhibits proteasomal degradation. Clinical analysis shows that patients co-expression of MEK1 and SIRT1 are associated with poor survival. Our finding indicates that MEK1-SIRT1 can act as a novel diagnostic biomarker and inhibition of MEK1 may be a viable therapeutic option for targeting liver CSCs treatment. PMID:26967560

  10. Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages

    PubMed Central

    Huber, Roman; Meier, Barbara; Otsuka, Atsushi; Fenini, Gabriele; Satoh, Takashi; Gehrke, Samuel; Widmer, Daniel; Levesque, Mitchell P.; Mangana, Joanna; Kerl, Katrin; Gebhardt, Christoffer; Fujii, Hiroko; Nakashima, Chisa; Nonomura, Yumi; Kabashima, Kenji; Dummer, Reinhard; Contassot, Emmanuel; French, Lars E.

    2016-01-01

    Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target. PMID:27426915

  11. Plant-microbe interactions promoting plant growth and health: perspectives for controlled use of microorganisms in agriculture.

    PubMed

    Berg, Gabriele

    2009-08-01

    Plant-associated microorganisms fulfill important functions for plant growth and health. Direct plant growth promotion by microbes is based on improved nutrient acquisition and hormonal stimulation. Diverse mechanisms are involved in the suppression of plant pathogens, which is often indirectly connected with plant growth. Whereas members of the bacterial genera Azospirillum and Rhizobium are well-studied examples for plant growth promotion, Bacillus, Pseudomonas, Serratia, Stenotrophomonas, and Streptomyces and the fungal genera Ampelomyces, Coniothyrium, and Trichoderma are model organisms to demonstrate influence on plant health. Based on these beneficial plant-microbe interactions, it is possible to develop microbial inoculants for use in agricultural biotechnology. Dependent on their mode of action and effects, these products can be used as biofertilizers, plant strengtheners, phytostimulators, and biopesticides. There is a strong growing market for microbial inoculants worldwide with an annual growth rate of approximately 10%. The use of genomic technologies leads to products with more predictable and consistent effects. The future success of the biological control industry will benefit from interdisciplinary research, e.g., on mass production, formulation, interactions, and signaling with the environment, as well as on innovative business management, product marketing, and education. Altogether, the use of microorganisms and the exploitation of beneficial plant-microbe interactions offer promising and environmentally friendly strategies for conventional and organic agriculture worldwide. PMID:19568745

  12. Promotion of plant growth by Pseudomonas fluorescens strain SS101 via novel volatile organic compounds.

    PubMed

    Park, Yong-Soon; Dutta, Swarnalee; Ann, Mina; Raaijmakers, Jos M; Park, Kyungseok

    2015-05-29

    Volatile organic compounds (VOCs) from plant growth-promoting rhizobacteria (PGPR) play key roles in modulating plant growth and induced systemic resistance (ISR) to pathogens. Despite their significance, the physiological functions of the specific VOCs produced by Pseudomonas fluorescens SS101 (Pf.SS101) have not been precisely elucidated. The effects of Pf.SS101 and its VOCs on augmentation of plant growth promotion were investigated in vitro and in planta. A significant growth promotion was observed in plants exposed Pf.SS101 under both conditions, suggesting that its VOCs play a key role in promoting plant growth. Solid-phase micro-extraction (SPME) and a gas chromatography-mass spectrophotometer (GC-MS) system were used to characterize the VOCs emitted by Pf.SS101 and 11 different compounds were detected in samples inoculated this bacterium, including 13-Tetradecadien-1-ol, 2-butanone and 2-Methyl-n-1-tridecene. Application of these compounds resulted in enhanced plant growth. This study suggests that Pf.SS101 promotes the growth of plants via the release of VOCs including 13-Tetradecadien-1-ol, 2-butanone and 2-Methyl-n-1-tridecene, thus increasing understanding of the role of VOCs in plant-bacterial inter-communication. PMID:25892516

  13. Synergistic interaction between the fibroblast growth factor and bone morphogenetic protein signaling pathways in lens cells

    PubMed Central

    Boswell, Bruce A.; Musil, Linda S.

    2015-01-01

    Fibroblast growth factors (FGFs) play a central role in two processes essential for lens transparency—fiber cell differentiation and gap junction–mediated intercellular communication (GJIC). Using serum-free primary cultures of chick lens epithelial cells (DCDMLs), we investigated how the FGF and bone morphogenetic protein (BMP) signaling pathways positively cooperate to regulate lens development and function. We found that culturing DCDMLs for 6 d with the BMP blocker noggin inhibits the canonical FGF-to-ERK pathway upstream of FRS2 activation and also prevents FGF from stimulating FRS2- and ERK-independent gene expression, indicating that BMP signaling is required at the level of FGF receptors. Other experiments revealed a second type of BMP/FGF interaction by which FGF prom