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1

Keratinocyte growth factor and coeliac disease  

Microsoft Academic Search

BACKGROUNDCoeliac disease is characterised by increased epithelial renewal associated with a mucosal T cell response to gliadin. Keratinocyte growth factor (KGF) is produced by cytokine activated gut stromal cells and may be a link between mucosal T cell activation in untreated coeliac disease and epithelial hyperplasia.AIMSTo characterise expression of KGF in coeliac disease.METHODSKGF transcripts in coeliac disease were measured by

V M Salvati; M Bajaj-Elliott; R Poulsom; G Mazzarella; K E A Lundin; E M Nilsen; R Troncone; T T MacDonald

2001-01-01

2

Expression and Function of Nerve Growth Factor and Nerve Growth Factor Receptor on Cultured Keratinocytes  

Microsoft Academic Search

Keratinocytes, a key cellular component both for homeostasis and pathophysiologic processes of the skin, secrete a number of cytokines and are stimulated by several growth factors. Nerve growth factor (NGF) is synthesized in the skin and basal keratinocytes express the low-affinity nerve growth factor receptor (NGF-R). We present evidence that normal human keratinocytes in culture express the low- and the

Carlo Pincelli; Cinzia Sevignani; Rossella Manfredini; Alexis Grande; Fabrizio Fantini; Luisa Bracci-Laudiero; Luigi Aloe; Sergio Ferrari; Andrea Cossarizza; Alberto Giannetti

1994-01-01

3

Fibroblast Growth Factor 10 Induces Proliferation and Differentiation of Human Primary Cultured Keratinocytes  

Microsoft Academic Search

Fibroblast growth factor 10 is a novel member of the fibroblast growth factor family, which is involved in morphogenesis and epithelial proliferation. It is highly homologous to the keratinocyte growth factor (or fibroblast growth factor 7), a key mediator of keratinocyte growth and differentiation. Both fibroblast growth factor 10 and keratinocyte growth factor bind with high affinity to the tyrosine

Cinzia Marchese; Alessandra Felici; Vincenzo Visco; Giuseppe Lucania; Makoto Igarashi; Mauro Picardo; Luigi Frati; Maria Rosaria Torrisi

2001-01-01

4

Expression of Keratinocyte Growth Factor in Periapical Lesions  

Microsoft Academic Search

The epithelial proliferation associated with inflammatory periapical lesions and with periapical cyst formation represents an interesting but poorly understood pathological change. Keratinocyte growth factor (KGF) is a recently identified growth factor that is produced by stromal fibroblasts and acts specifically to stimulate epithelial growth and differentiation. To investigate its possible role in the activation of the normally quiescent rests of

Z. Gao; C. M. Flaitz; I. C. Mackenzie

1996-01-01

5

Keratinocyte Growth Factor Improves Repair in the Injured Tracheal Epithelium  

Microsoft Academic Search

Keratinocyte growth factor (KGF) is a critical growth factor in lung development and is a protective agent after lung injury, although the exact mechanisms of this protective effect have not yet been elucidated. Our laboratory has shown that circulating epithelial progenitor cells can traffic to the airway and that they appear to be derived from the bone marrow. On this

Brigitte N. Gomperts; John A. Belperio; Michael C. Fishbein; Michael P. Keane; Marie D. Burdick; Robert M. Strieter

2007-01-01

6

Modulation of calprotectin in human keratinocytes by keratinocyte growth factor and interleukin-1alpha.  

PubMed

Calprotectin is an antimicrobial complex composed of the S100A8 and S100A9 protein family subunits. Contributing to innate immunity, calprotectin expression is increased by interleukin-1alpha (IL-1alpha), which modulates keratinocyte differentiation. Keratinocyte growth factor (KGF) is produced by mesenchymal cells and has a mitogenic activity for epithelial cells. In this study, we investigated the effect of KGF on calprotectin expression in keratinocytes and modulation by IL-1alpha. Human keratinocytes were cultured with KGF in the presence or absence of a KGF receptor (KGFR) inhibitor or mitogen-activated protein kinase (MAPK) inhibitors. Calprotectin (S100A8/S100A9) expression was determined by northern blotting and enzyme-linked immunosorbent assay, respectively, whereas MAPK phosphorylation was analyzed by western blot analysis. KGF significantly decreased the expression of S100A8/S100A9-specific mRNAs and calprotectin protein. In the presence of KGF, KGFR inhibitor or extracellular-regulated kinase inhibitor restored KGF-downregulated expression of S100A8/S100A9. KGF increased IL-1alpha expression in keratinocytes, whereas IL-1alpha increased KGF expression in fibroblasts. Cocultured fibroblast and keratinocytes showed lower S100A8/S100A9 mRNA expression than keratinocytes alone in the presence or absence of IL-1alpha or KGF. These results suggest that fibroblast-derived KGF reduces or restricts calprotectin expression in keratinocytes, which supports our hypothesis that calprotectin expression in keratinocytes is modulated by factors associated with epithelial-mesenchymal interactions. PMID:20065999

Bando, Mika; Hiroshima, Yuka; Kataoka, Masatoshi; Herzberg, Mark C; Ross, Karen F; Shinohara, Yasuo; Yamamoto, Takenori; Nagata, Toshihiko; Kido, Jun-ichi

2010-01-01

7

Hepatocyte Growth Factor, Keratinocyte Growth Factor, Their Receptors, Fibroblast Growth Factor Receptor2, and the Cells of the Cornea  

Microsoft Academic Search

Purpose. The purpose of this study was to determine whether messenger RNA coding for hepatocyte growth factor (HGF), HGF receptor (MET), keratinocyte growth factor (KGF), KGF receptor, and fibroblast growth factor (FGF) receptor-2 were produced in primary cul- tures of human corneal epithelial, stromal fibroblast, and endothelial cells, as well as ex vivo corneal epithelium, endothelial cells transfected with the

Steven E. Wilson; Joel W. Walker; Eric L. Chwang; Yu-Guang He

8

Crucial Effects of Fibroblasts and Keratinocyte Growth Factor on Morphogenesis of Reconstituted Human Oral Epithelium  

Microsoft Academic Search

The connective tissue is known to have a general supportive effect for the development of the overlying epithelium; however, the more specific effects of fibroblasts and the involvement of their product, keratinocyte growth factor, on oral epithelial morphogenesis have not yet been addressed. Therefore, the purpose of this study was to investigate the effects of fibroblasts and keratinocyte growth factor

Daniela Elena Costea; Lado Lako Loro; Elisabeth Anne Okumo Dimba; Olav Karsten Vintermyr; Anne Christine Johannessen

2003-01-01

9

Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3.  

PubMed

Keratinocyte growth factor (KGF) activates keratinocyte migration and stimulates wound healing. Hyaluronan, an extracellular matrix glycosaminoglycan that accumulates in wounded epidermis, is known to promote cell migration, suggesting that increased synthesis of hyaluronan might be associated with the KGF response in keratinocytes. Treatment of monolayer cultures of rat epidermal keratinocytes led to an elongated and lifted cell shape, increased filopodial protrusions, enhanced cell migration, accumulation of intermediate size hyaluronan in the culture medium and within keratinocytes, and a rapid increase of hyaluronan synthase 2 (Has2) mRNA, suggesting a direct influence on this gene. In stratified, organotypic cultures of the same cell line, both Has2 and Has3 with the hyaluronan receptor CD44 were up-regulated and hyaluronan accumulated in the epidermis, the spinous cell layer in particular. At the same time the expression of the early differentiation marker keratin 10 was inhibited, whereas filaggrin expression and epidermal permeability were less affected. The data indicate that Has2 and Has3 belong to the targets of KGF in keratinocytes, and support the idea that enhanced hyaluronan synthesis acts an effector for the migratory response of keratinocytes in wound healing, whereas it may delay keratinocyte terminal differentiation. PMID:14506240

Karvinen, Susanna; Pasonen-Seppänen, Sanna; Hyttinen, Juha M T; Pienimäki, Juha-Pekka; Törrönen, Kari; Jokela, Tiina A; Tammi, Markku I; Tammi, Raija

2003-12-01

10

Keratinocyte Growth Factor Improves Repair in the Injured Tracheal Epithelium  

PubMed Central

Keratinocyte growth factor (KGF) is a critical growth factor in lung development and is a protective agent after lung injury, although the exact mechanisms of this protective effect have not yet been elucidated. Our laboratory has shown that circulating epithelial progenitor cells can traffic to the airway and that they appear to be derived from the bone marrow. On this basis, we hypothesized that KGF and its putative receptor (KGFR) would be important to these cells. We showed that the KGFR, which is found almost exclusively on epithelial cells, was present on cells in the bone marrow and circulation of mice that identified a subpopulation of cytokeratin 5+ circulating epithelial progenitor cells (CEPC). In addition, the KGFR co-localized with a population of cytokeratin 5+ basal cells in the repairing proximal airway. Systemic administration of KGF resulted in a significant increase in mobilization of cytokeratin 5+ CEPC at 6 h after injection. Administration of KGF to mouse recipients of heterotopic syngeneic tracheal transplants resulted in protection and more rapid repair of the tracheal epithelium, with an increase in the number of CEPC in the epithelium of the airway, and this effect was abrogated by blocking CEPC with anti-CXCL12 antibodies. KGF therefore appears to be an important growth factor for local resident progenitor epithelial cell repair and for mobilization and enhanced engraftment of CEPC to the injured proximal airway epithelium. PMID:17332441

Gomperts, Brigitte N.; Belperio, John A.; Fishbein, Michael C.; Keane, Michael P.; Burdick, Marie D.; Strieter, Robert M.

2007-01-01

11

Keratinocyte growth factor improves repair in the injured tracheal epithelium.  

PubMed

Keratinocyte growth factor (KGF) is a critical growth factor in lung development and is a protective agent after lung injury, although the exact mechanisms of this protective effect have not yet been elucidated. Our laboratory has shown that circulating epithelial progenitor cells can traffic to the airway and that they appear to be derived from the bone marrow. On this basis, we hypothesized that KGF and its putative receptor (KGFR) would be important to these cells. We showed that the KGFR, which is found almost exclusively on epithelial cells, was present on cells in the bone marrow and circulation of mice that identified a subpopulation of cytokeratin 5+ circulating epithelial progenitor cells (CEPC). In addition, the KGFR co-localized with a population of cytokeratin 5+ basal cells in the repairing proximal airway. Systemic administration of KGF resulted in a significant increase in mobilization of cytokeratin 5+ CEPC at 6 h after injection. Administration of KGF to mouse recipients of heterotopic syngeneic tracheal transplants resulted in protection and more rapid repair of the tracheal epithelium, with an increase in the number of CEPC in the epithelium of the airway, and this effect was abrogated by blocking CEPC with anti-CXCL12 antibodies. KGF therefore appears to be an important growth factor for local resident progenitor epithelial cell repair and for mobilization and enhanced engraftment of CEPC to the injured proximal airway epithelium. PMID:17332441

Gomperts, Brigitte N; Belperio, John A; Fishbein, Michael C; Keane, Michael P; Burdick, Marie D; Strieter, Robert M

2007-07-01

12

Large Induction of Keratinocyte Growth Factor Expression in the Dermis During Wound Healing  

Microsoft Academic Search

Recent studies have shown that application of basic fibroblast growth factor (basic FGF) to a wound has a beneficial effect. However, it has not been assessed whether endogenous FGF also plays a role in tissue repair. In this study we found a 160-fold induction of mRNA encoding keratinocyte growth factor (KGF) 1 day after skin injury. This large induction was

Sabine Werner; Kevin G. Peters; Michael T. Longaker; Frances Fuller-Pace; Michael J. Banda; Lewis T. Williams

1992-01-01

13

Insulin-like growth factor-I and UVB photoprotection in human keratinocytes.  

PubMed

Ultraviolet radiation (UVR), in particular the UVB spectrum, is a risk factor for skin cancer development. The generation and accumulation of UVB-induced genetic mutations are fundamental premalignant events. Keratinocyte interactions between other cutaneous cell populations and the surrounding microenvironment determine cell fate and acute photoresponses. In this study, the importance of the insulin-like growth factor (IGF) system, in particular the insulin-like growth factor-I (IGF-I), on influencing key processes in the keratinocyte acute photoresponse was investigated. Exogenous IGF-I and other growth factors present in dermal fibroblast-conditioned media (CM) were found to significantly enhance keratinocyte survival following UVB irradiation in vitro. This pretreatment was also shown to cause a shift in the expression levels of various DNA damage response proteins. Consequently, this was associated with accelerated rates of UVB-induced cyclobutane pyrimidine dimer removal in these samples. Finally, activation of the IGF system influenced cell cycle progression in UVB-irradiated keratinocytes. Taken together, these results highlight the importance of the IGF signalling network in initiating the repair of potentially mutagenic DNA damage in human keratinocytes. The dysregulation of these processes may therefore have significant implications in the aetiology of skin cancers and other cutaneous diseases. PMID:25607472

Fernandez, Tara Lyn; Van Lonkhuyzen, Derek R; Dawson, Rebecca A; Kimlin, Michael G; Upton, Zee

2015-03-01

14

Keratinocyte growth factor signalling: a mathematical model of dermalepidermal interaction in epidermal wound healing  

E-print Network

in epidermal wound healing Helen J. Wearing *, Jonathan A. Sherratt Centre for Theoretical Modelling of their therapeutic value is essential to achieve improved wound healing. Keratinocyte growth factor (KGF) seems cells, yet acts exclusively on epithelial cells. In this paper, we study KGF's role in epidermal wound

Rohani, Pejman

15

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor.  

PubMed

Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFN?, IL-1?, IL-4, IL-6, IL-17A, IL-22 or TNF?. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFN?, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. PMID:25617811

Bae, Ok-Nam; Ahn, Seyeon; Jin, Sun Hee; Hong, Soo Hyun; Lee, Jinyoung; Kim, Eun-Sun; Jeong, Tae Cheon; Chun, Young-Jin; Lee, Ai-Young; Noh, Minsoo

2015-03-01

16

Latent and Active Transforming Growth Factor ?1 Released from Genetically Modified Keratinocytes Modulates Extracellular Matrix Expression by Dermal Fibroblasts in a Coculture System  

Microsoft Academic Search

Transforming growth factor ?1 is a multifunctional cytokine involved in many aspects of wound healing. Here we report the effects of both latent and active transforming growth factor ?1 released from genetically modified keratinocytes on extracellular matrix expression by dermal fibroblasts in a coculture system. Human keratinocytes were genetically modified with adenovirus containing cDNA for latent transforming growth factor ?1

Barbara S. Bauer; Edward E. Tredget; Yvonne Marcoux; Paul G. Scott; Aziz Ghahary

2002-01-01

17

Keratinocytic Vascular Endothelial Growth Factor as a Novel Biomarker for Pathological Skin Condition  

PubMed Central

Skin is an emerging target tissue in pharmaceutical and cosmetic science. Safety assessment for dermal toxicity is a critical step for development of topically applicable pharmaceutical agents and ingredients in cosmetics. Urgent needs exist to set up toxicity testing methods for dermal safety, and identification of novel biomarkers for pathological cutaneous alteration is highly required. Here we will discuss if vascular endothelial growth factor (VEGF) has a potential as a biomarker for dermal impairment. Experimental and clinical evidences for induction of keratinocytic VEGF under pathological conditions will be reviewed. PMID:25593638

Bae, Ok-Nam; Noh, Minsoo; Chun, Young-Jin; Jeong, Tae Cheon

2015-01-01

18

Lactose Induction Increases Production of Recombinant Keratinocyte Growth Factor2 in Escherichia coli  

Microsoft Academic Search

Recombinant human keratinocyte growth factor-2 (rhKGF-2) has previously been expressed in Escherichia coli using isopropyl-?-d-thiogalactopyranoside (IPTG), a non-metabolizable and expensive compound, as the inducer. In order to determine whether IPTG\\u000a could be replaced with the cheap and natural lactose to induce rhKGF-2 expression, we examined the expression of rhKGF-2 in\\u000a flask culture and 30-l fermentation using lactose as the inducer.

Haishan TianLu; Lu Tang; Yi Wang; Xiaojie Wang; Lili Guan; Jian Zhang; Xiaoping Wu; Xiaokun Li

2011-01-01

19

Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium.  

PubMed Central

Epithelial-mesenchymal interactions mediate aspects of normal lung growth and development and are important in the restoration of normal alveolar architecture after lung injury. To determine if fibroblasts are a source of soluble growth factors for alveolar type II cells, we investigated the effect of fibroblast-conditioned medium (CM) on alveolar type II cell DNA synthesis. Serum-free CM from confluent adult human lung fibroblasts was concentrated fivefold by lyophilization. Type II cells were isolated from adult rats by elastase dissociation and incubated with [3H]thymidine and varying dilutions of concentrated CM and serum from day 1 to 3 of culture. Stimulation of type II cell DNA synthesis by fibroblast-CM was maximal after 48 h of conditioning and required the presence of serum. The activity of the CM was eliminated by boiling and by treatment with trypsin, pepsin, or dithiothreitol and was additive with saturating concentrations of acidic fibroblast growth factor, epidermal growth factor, and insulin. The growth factor activity bound to heparin-Sepharose and was eluted with 0.6 and 1.0 M NaCl. Neutralizing antibody studies demonstrated that the primary mitogens isolated in the 0.6 and 1.0 M NaCl fractions were keratinocyte growth factor (KGF, fibroblast growth factor 7) and hepatocyte growth factor/scatter factor (HGF/SF), respectively. HGF/SF was demonstrated in the crude CM and KGF was detected in the 0.6 M NaCl eluent by immunoblotting. Northern blot analysis confirmed that the lung fibroblasts expressed both KGF and HGF/SF transcripts. Human recombinant KGF and HGF/SF induced a concentration- and serum-dependent increase in rat alveolar type II cell DNA synthesis. We conclude that adult human lung fibroblasts produce at least two soluble heparin-binding growth factors, KGF and HGF/SF, which promote DNA synthesis and proliferation of rat alveolar type II cells in primary culture. KGF and HGF/SF may be important stimuli for alveolar type II cell proliferation during lung growth and after lung injury. Images PMID:7688769

Panos, R J; Rubin, J S; Csaky, K G; Aaronson, S A; Mason, R J

1993-01-01

20

An overview on keratinocyte growth factor: from the molecular properties to clinical applications.  

PubMed

KGF (Keratinocyte Growth Factor), also known as FGF7, is a potent mitogen for different types of epithelial cells, which regulates migration and differentiation of these cells and protects them from various insults under stress conditions. KGF is produced by mesenchymal cells and exerts its biological effects via binding to its high-affinity receptor, a splice variant of FGF receptor 2 (FGFR2-IIIb), which is expressed by various types of epithelial cells, including epidermal keratinocytes, intestinal epithelial cells, and hepatocytes. This expression pattern of KGF and its receptor suggests that KGF acts predominantly in a paracrine manner. After acute injury, in various tissues--including the skin, the bladder as well as in chronically injured tissue--KGF expression is strongly up-regulated. This up-regulation is likely to be important for the healing of injured epithelia. In addition, KGF could also exert a protective effect on these cells. There are many researches have been underway to identify clinical applications for KGF. Specifically, KGF is currently being evaluated in clinical trials sponsored by Amgen (Thousand Oaks, CA) to test its ability to ameliorate severe oral mucositis (OM) that results from cancer chemoradiotherapy. In this paper, we provide an overview of the knowledge on molecular properties, biological functions and the recent findings on clinical application of KGF. PMID:24188496

Yen, Tran Thi Hai; Thao, Dang Thi Phuong; Thuoc, Tran Linh

2014-03-01

21

Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor  

Microsoft Academic Search

Chronic exposure to ultraviolet (UV) irradiation induces skin cancer, in part, through epigenetic mechanisms that result in the deregulation of cell proliferation. UV irradi- ation also rapidly activates the epidermal growth factor receptor (EGFR). Since EGFR activation is strongly mito- genic in many cell types including keratinocytes of the skin, we hypothesized that UV-induced cutaneous proliferation results from EGFR activation.

Taghrid B. El-Abaseri; Sumanth Putta; Laura A. Hansen

2006-01-01

22

Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in vascular smooth muscle cells.  

PubMed

Keratinocyte growth factor receptor (KGFR), also known as fibroblast growth factor receptor (FGFR)2 IIIb, is located in many types of epithelial cells and is activated by four known ligands (FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10) that are predominantly synthesized by mesenchymal cells. In the early stage of atherosclerosis, vascular smooth muscle cells (VSMC) transform from a contractile to a synthetic phenotype, proliferate and migrate into the intima. Previously, FGF-7 mRNA expression was reported in VSMC, but KGFR mRNA was not detected. In the present study, we attempted to determine whether KGFR is localized in VSMC cultured from rat aorta and VSMC in human normal and atherosclerotic coronary arteries. Expression of KGFR mRNA and its protein was detected in cultured rat VSMC by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Immunohistochemically, KGFR was localized in the VSMC of the outer layer of the media in normal human coronary arteries. Furthermore, it was localized in the VSMC of the media and thickened intima of atherosclerotic arteries. Recombinant FGF-7 and/or FGF-10 proteins stimulated the growth of cultured rat VSMC. These findings indicate that KGFR localized in VSMC may contribute to the proliferation of VSMC in normal and atherosclerotic arteries. PMID:12608893

Onda, Munehiko; Naito, Zenya; Wang, Ruojiao; Fujii, Takenori; Kawahara, Kiyoko; Ishiwata, Toshiyuki; Sugisaki, Yuichi

2003-03-01

23

Recombinant Keratinocyte Growth Factor 1 in Tobacco Potentially Promotes Wound Healing in Diabetic Rats  

PubMed Central

Keratinocyte growth factor 1 (KGF1) is a growth factor that promotes epidermal cell proliferation, migration, differentiation, and wound repair. It is expressed at low levels in a form of inclusion body in E. coli. In order to increase its expression and activity, we produced tobacco plants expressing KGF1 via Agrobacterium-mediated transformation using a potato virus X (PVX)-based vector (pgR107). The vector contained the sequence encoding the KGF1 gene fused with a green florescence protein. The recombinant plasmid was introduced into leaf cells of Nicotiana benthamiana (a wild Australian tobacco) via Agrobacterium-mediated agroinfiltration. As determined by fluorescence and Western blot of leaf extracts, the KGF1 gene was correctly translated into the tobacco plants. The recombinant KGF1 was purified from plant tissues by heparin affinity chromatography, and cell proliferation in NIH/3T3 cells was stimulated by the purified KGF1. The purified KGF1 was also applied to the wounds of type-II diabetic rats. KGF1 had accumulated to levels as high as 530??g/g fresh weight in the leaves of agroinfected plants. We show that plant-derived KGF1 can promote the proliferation of NIH/3T3 cells and have significant effects on the type-II diabetic rat. The present findings indicated that KGF1 from tobacco maintains its biological activity, implying prospective industrial production in a plant bioreactor. PMID:24783215

Feng, Zhi-Guo; Pang, Shi-Feng; Guo, Ding-Jiong; Yang, Yue-Tao; Liu, Bin; Wang, Ji-Wei; Zheng, Ke-Qin; Lin, Yi

2014-01-01

24

Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing.  

PubMed Central

Keratinocyte growth factor (KGF) has been implicated in wound re-epithelialization and branching morphogenesis of several organs. To determine whether KGF induces these effects via induction of matrix metalloproteinase expression we have analysed the effect of KGF on the expression of stromelysin-2 in cultured HaCaT keratinocytes. Here we show a strong induction of stromelysin-2 mRNA within 5-8 h of stimulation of these cells with KGF. The degree of induction was similar to that achieved by treatment with epidermal growth factor or tumour necrosis factor alpha, whereas the stimulatory effect of transforming growth factor beta 1 was even stronger. To determine whether the induction of stromelysin-2 expression by growth factors and cytokines might be important for wound healing, we analysed the expression of this gene during the healing process of full-thickness excisional wounds in mice. Whereas stromelysin-2 mRNA could hardly be detected in unwounded skin, a biphasic induction was seen after injury and highest levels were found at days 1 and 5 after wounding. Hybridization in situ revealed the presence of stromelysin-2 mRNA in basal keratinocytes at the wound edge but not in the underlying mesenchymal tissue. During impaired wound healing as seen in glucocorticoid-treated mice, stromelysin-2 expression was significantly increased compared with untreated control mice. Taken together, these results suggest that correct regulation of this broad-spectrum metalloproteinase might be important for normal repair. PMID:8973581

Madlener, M; Mauch, C; Conca, W; Brauchle, M; Parks, W C; Werner, S

1996-01-01

25

Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in human uterine cervical cancer.  

PubMed

Keratinocyte growth factor receptor (KGFR), also known as FGFR2 IIIb, is a splice variant of FGFR-2. KGFR is expressed in many types of epithelial cell and is activated with four known ligands [FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10] that are predominantly synthesized by mesenchymal cells. KGFR is highly expressed in the late-proliferative phase of a normal endometrium and in endometrial adenocarcinoma. In the present study, we attempted to determine the expression and localization of KGFR in human cervical cancer cell lines and cervical cancer tissues. The KGFR protein was detected in CaSki and HeLa cells, but not in ME-180 cells of cervical cancer cell lines. In non-cancer cervical tissues, KGFR immunoreactivity was weakly expressed in the surface of squamous epithelial cells and vascular smooth muscle cells. Immunohistochemically, the KGFR protein was detected in squamous cell carcinoma in 36 of 42 (86%) cervical cancer patients. In cervical cancer tissues, KGFR was detected in 17 of 18 (94%) of patients with the keratinizing type and 19 of 24 (79%) of patients with the non-keratinizing type of cervical cancer. Furthermore, KGFR was prominently localized in proliferating reserve cells and squamous metaplastic reserve cells adjacent to cancer cells. In contrast, KGFR was not detected in cervical ductal cells in cancer or non-cancer cervical tissues. These findings may indicate that KGFR mediates the growth and differentiation of reserve cells and squamous cell carcinoma in the cervix. PMID:15069536

Kurban, Gulnar; Ishiwata, Toshiyuki; Kudo, Mitsuhiro; Yokoyama, Munehiro; Sugisaki, Yuichi; Naito, Zenya

2004-05-01

26

Effects of MAP Kinase Inhibitors on Epidermal Growth Factor-Induced Neoplastic Transformation of Human Keratinocytes  

PubMed Central

We previously reported data regarding the mechanism of neoplastic transformation in JB6 Cl41 mouse skin epidermal cells. However, experimental in vitro models for studying neoplastic transformation of human cells could provide further insight into the mechanisms of human cancer development. In this study, we have established a neoplastic transformation model with HaCaT cells, a human keratinocyte cell line, and showed the usefulness of this cell line for studying the mechanisms of neoplastic transformation. Epidermal growth factor (EGF) treatment induced a dose-dependent anchorage-independent cell transformation in HaCaT cells. Furthermore, PD98059, a MAP kinase/ERK kinase (MEK) inhibitor, or SP600125, c-Jun N-terminal kinase (JNK) inhibitor, decreased cell growth, EGF-induced DNA synthesis and transformation. Unlike observations in the JB6 mouse epidermal cell model, SB203580, a stress-activated protein kinase-2/p38 ? and ? (p38) inhibitor, increased EGF-induced transformation in HaCaT cells. These results suggest that extracellular-signal regulated kinase (ERK), JNK or p38 are implicated in EGF-induced neoplastic transformation of human cells. PMID:16302268

Mizuno, Hideya; Cho, Yong-Yeon; Ma, Wei-Ya; Bode, Ann M.; Dong, Zigang

2006-01-01

27

Evidence for the presence of keratinocyte growth factor (KGF) in human ovarian follicles.  

PubMed

The presence of keratinocyte growth factor (KGF) in human follicular fluid (FF) was investigated in a total of 145 FFs obtained during oocyte retrieval for in vitro fertilization (IVF) from 29 patients with no apparent endocrine disorders. The concentrations of KGF, estradiol, progesterone, testosterone and human chorionic gonadotropin (hCG) in FF were measured by enzyme-linked immunosorbent assay. FF samples contained relatively higher amounts of KGF (2194+/-87 pg/ml), whereas its concentrations in serum were below assay limit (<31.2 pg/ml). Concentrations of KGF in FF were positively correlated with both progesterone (r=0.311, p<0.0005) and testosterone (r=0.230, p<0.01) concentrations in FF. However, KGF concentrations were not significantly correlated with estradiol and hCG concentrations. KGF in FF was detected as a broad band (26-29 kD) by immunoblotting, the size being reduced by 7kD after N-glycosidase treatment. In an in vitro experiment, KGF suppressed the basal and hCG-stimulated progesterone production by cultured human luteinized granulosa cells. summary, we demonstrated the presence of KGF in human ovarian follicles, suggesting its possible role as a local factor in regulating human ovarian functions. PMID:11456262

Osuga, Y; Koga, K; Tsutsumi, O; Yano, T; Kugu, K; Momoeda, M; Okagaki, R; Suenaga, A; Fujiwara, T; Fujimoto, A; Matsumi, H; Hiroi, H; Taketani, Y

2001-04-01

28

Pulmonary malformation in transgenic mice expressing human keratinocyte growth factor in the lung.  

PubMed Central

Expression of human keratinocyte growth factor (KGF/FGF-7) was directed to epithelial cells of the developing embryonic lung of transgenic mice disrupting normal pulmonary morphogenesis during the pseudoglandular stage of development. By embryonic day 15.5(E15.5), lungs of transgenic surfactant protein C (SP-C)-KGF mice resembled those of humans with pulmonary cystadenoma. Lungs were cystic, filling the thoracic cavity, and were composed of numerous dilated saccules lined with glycogen-containing columnar epithelial cells. The normal distribution of SP-C proprotein in the distal regions of respiratory tubules was disrupted. Columnar epithelial cells lining the papillary structures stained variably and weakly for this distal respiratory cell marker. Mesenchymal components were preserved in the transgenic mouse lungs, yet the architectural relationship of the epithelium to the mesenchyme was altered. SP-C-KGF transgenic mice failed to survive gestation to term, dying before E17.5. Culturing mouse fetal lung explants in the presence of recombinant human KGF also disrupted branching morphogenesis and resulted in similar cystic malformation of the lung. Thus, it appears that precise temporal and spatial expression of KGF is likely to play a crucial role in the control of branching morphogenesis during fetal lung development. Images Fig. 1 Fig. 2 Fig. 3 PMID:8618921

Simonet, W S; DeRose, M L; Bucay, N; Nguyen, H Q; Wert, S E; Zhou, L; Ulich, T R; Thomason, A; Danilenko, D M; Whitsett, J A

1995-01-01

29

Keratinocyte growth factor-2 (FGF-10) promotes healing of experimental small intestinal ulceration in rats.  

PubMed

Keratinocyte growth factor-2 (KGF-2, repifermin) is a homolog of KGF-1 with epithelial mitogenic activities. We investigated the therapeutic role of KGF-2 in intestinal ulceration and its mechanisms of protection. KGF-2 (0.3-5 mg/kg) was administered before or after induction of small intestinal ulceration by indomethacin (Indo) in prevention and treatment protocols. In acute studies, KGF-2 was injected for up to 7 days before or daily for 5 days after Indo. In a 15-day chronic study, KGF-2 was injected intravenously daily beginning before or 7 days after Indo. Injury was evaluated by blinded macroscopic and microscopic inflammatory scores, epithelial BrdU staining, tissue IL-1beta, PGE(2), and hydroxyproline concentrations, and collagen type I RNA expression. In vitro effects of KGF-2 were evaluated by epithelial cellular proliferation, restitution of wounded monolayers, PGE(2) secretion, and expression of COX-2 and collagen mRNA. Intravenous KGF-2 significantly decreased acute intestinal injury by all parameters and significantly decreased chronic ulceration. Pretreatment, daily infusion, and delayed treatment were effective. KGF-2 promoted in vitro epithelial restitution with only modest effects on epithelial cell proliferation, stimulated COX-2 expression in cultured epithelial cells, and upregulated in vitro and in vivo PGE(2) production. KGF-2 did not affect in vivo fibrosis, although it induced collagen expression in cultured intestinal myofibroblasts. These results suggest that KGF-2 inhibits intestinal inflammation by stimulating epithelial restitution and protective PGs. PMID:11052999

Han, D S; Li, F; Holt, L; Connolly, K; Hubert, M; Miceli, R; Okoye, Z; Santiago, G; Windle, K; Wong, E; Sartor, R B

2000-11-01

30

Strengthening the Skin with Topical Delivery of Keratinocyte Growth Factor-1 Using a Novel DNA Plasmid  

PubMed Central

Fragile skin, susceptible to decubitus ulcers and incidental trauma, is a problem particularly for the elderly and for those with spinal cord injury. Here, we present a simple approach to strengthen the skin by the topical delivery of keratinocyte growth factor-1 (KGF-1) DNA. In initial feasibility studies with the novel minimalized, antibiotic-free DNA expression vector, NTC8385-VA1, the reporter genes luciferase and enhanced green fluorescent protein were delivered. Transfection was documented when luciferase expression significantly increased after transfection. Microscopic imaging of enhanced green fluorescent protein–transfected skin showed green fluorescence in hair follicles, hair shafts, and dermal and superficial epithelial cells. With KGF-1 transfection, KGF-1 mRNA level and protein production were documented with quantitative reverse transcriptase–polymerase chain reaction and immunohistochemistry, respectively. Epithelial thickness of the transfected skin in the KGF group was significantly increased compared with the control vector group (26?±?2 versus 16?±?4 µm) at 48 hours (P = 0.045). Dermal thickness tended to be increased in the KGF group (255?±?36 versus 162?±?16 µm) at 120 hours (P = 0.057). Biomechanical assessment showed that the KGF-1–treated skin was significantly stronger than control vector–transfected skin. These findings indicate that topically delivered KGF-1 DNA plasmid can increase epithelial thickness and strength, demonstrating the potential of this approach to restore compromised skin. PMID:24434934

Dou, Chunqing; Lay, Frank; Ansari, Amir Mehdi; Rees, Donald J; Ahmed, Ali Karim; Kovbasnjuk, Olga; Matsangos, Aerielle E.; Du, Junkai; Hosseini, Sayed Mohammad; Steenbergen, Charles; Fox-Talbot, Karen; Tabor, Aaron T.; Williams, James A; Liu, Lixin; Marti, Guy P; Harmon, John W

2014-01-01

31

Keratinocyte growth factor-2 stimulates P-glycoprotein expression and function in intestinal epithelial cells  

PubMed Central

Intestinal P-glycoprotein (Pgp/multidrug resistance 1), encoded by the ATP-binding cassette B1 gene, is primarily involved in the transepithelial efflux of toxic metabolites and xenobiotics from the mucosa into the gut lumen. Reduced Pgp function and expression has been shown to be associated with intestinal inflammatory disorders. Keratinocyte growth factor-2 (KGF2) has emerged as a potential target for modulation of intestinal inflammation and maintenance of gut mucosal integrity. Whether KGF2 directly regulates Pgp in the human intestine is not known. Therefore, the present studies were undertaken to determine the modulation of Pgp by KGF2 using Caco-2 cells. Short-term treatment of Caco-2 cells with KGF2 (10 ng/ml, 1 h) increased Pgp activity (?2-fold, P < 0.05) as measured by verapamil-sensitive [3H]digoxin flux. This increase in Pgp function was associated with an increase in surface Pgp levels. The specific fibroblast growth factor receptor (FGFR) antagonist PD-161570 blocked the KGF2-mediated increase in Pgp activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD-98059 attenuated the stimulatory effects of KGF2 on Pgp activity. Small-interfering RNA knockdown of Erk1/2 MAPK blocked the increase in surface Pgp levels by KGF2. Long-term treatment with KGF2 (10 ng/ml, 24 h) also significantly increased PgP activity, mRNA, protein expression, and promoter activity. The long-term effects of KGF2 on Pgp promoter activity were also blocked by the FGFR antagonist and mediated by the Erk1/2 MAPK pathway. In conclusion, our findings define the posttranslational and transcriptional mechanisms underlying stimulation of Pgp function and expression by KGF2 that may contribute to the beneficial effects of KGF2 in intestinal inflammatory disorders. PMID:23328208

Priyamvada, Shubha; Kumar, Anoop; Akhtar, Maria; Soni, Vikas; Anbazhagan, Arivarasu Natarajan; Alakkam, Anas; Alrefai, Waddah A.; Dudeja, Pradeep K.; Gill, Ravinder K.

2013-01-01

32

Human keratinocyte growth factor effects in a porcine model of epidermal wound healing  

PubMed Central

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family (hence the alternative designation FGF-7). It is produced by stromal cells, but acts as a mitogen for epithelial cells. We examined the effects of topically applied KGF on healing of wounds in a porcine model. In partial-thickness wounds, KGF stimulated the rate of reepithelialization (p < 0.0002), associated with a thickening of the epidermis (p < 0.0001). Epidermis from KGF-treated full-thickness wound sites was significantly thicker (0.31 +/- 0.22 mm) compared with mirror image control sites (0.18 +/- 0.12 mm) (p < 0.0001). Moreover, the majority (77%) of KGF-treated wounds exhibited epidermis with a deep rete ridge pattern as compared with control sites. These effects were observed as early as 14 d and persisted for at least 4 wk. KGF treatment also increased the number of serrated basal cells associated with increased deposition of collagen fibers in the superficial dermis adjacent to the acanthotic epidermis. Electron microscopy revealed better developed hemidesmosomes associated with thicker bundles of tonofilaments in the serrated cells. The pattern of epidermal thickening observed in KGF-treated wounds resembled psoriasis. Psoriasis is a disease associated with epidermal thickening, parakeratosis as well as hyperproliferation that extends beyond the basal layer. In striking contrast to psoriasis, KGF-treated wounds exhibited normal orthokeratotic maturation, and proliferation was localized to the basal cells. Our present findings have significant implications concerning the role of KGF as a paracrine modulator of epidermal proliferation and differentiation. PMID:8350059

Staiano-Coico, L.; Krueger, J. G.; Rubin, J. S.; D'limi, S.; Vallat, V. P.; Valentino, L.; Fahey, T.; Hawes, A.; Kingston, G.; Madden, M. R.; Mathwich, M.; Gottlieb, A.; Aaronson, S. A.

1993-01-01

33

Keratinocyte Growth Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury  

PubMed Central

Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown. Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS. Methods: Volunteers were randomized to intravenous KGF (60 ?g/kg) or placebo for 3 days, before inhaling 50 ?g LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury. Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony–stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor. Conclusions: KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895. PMID:24716610

Shyamsundar, Murali; McAuley, Daniel F.; Ingram, Rebecca J.; Gibson, David S.; McKeown, Scott T.; Edwards, Alex; Taggart, Cliff; Elborn, Joseph S.; Calfee, Carolyn S.; Matthay, Michael A.

2014-01-01

34

Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways.  

PubMed

Sensory neurons innervating the skin can release neuropeptides that are believed to modulate cellular proliferation, wound healing, pigmentation, and keratinocyte innate immune responses. While the ability of neuropeptides to stimulate keratinocyte production of inflammatory mediators has been demonstrated, there is no information concerning the mechanisms by which neuropeptide activation of keratinocyte cell surface receptors ultimately leads to the up-regulation of mediator production. In this study we used a keratinocyte cell line to identify the presence of substance P (SP) and calcitonin gene-related peptide (CGRP) receptors on keratinocytes and examined the effects of SP and CGRP stimulation on keratinocyte neuropeptide signaling, cell proliferation, and interleukin-1? (IL-1?), interleukin-6 (IL-6), tumor necrosis factor ? (TNF-?), and nerve growth factor (NGF) expression. Neuropeptide stimulation caused an up-regulation of neuropeptide receptor expression in keratinocytes and a dramatic increase in keratinocyte secretion of SP and CGRP, suggesting possible autocrine or paracrine stimulatory effects and amplification of neuropeptide signaling. Both SP and CGRP concentration-dependently stimulated cellular proliferation and the expression and secretion of inflammatory cytokines and NGF in keratinocytes. SP also activated all 3 families of mitogen activated protein kinase (MAPK) and nuclear factor ?B (NF?B) in keratinocytes, while CGRP only activated p38 and extracellular signal related kinase1/2 (ERK1/2) MAPKs. Neuropeptide stimulated inflammatory mediatory production in keratinocytes was reversed by ERK1/2 and JNK inhibitors. The current study is the first to observe; 1) that CGRP stimulates keratinocyte expression of CGRP and its receptor complex, 2) that SP and CGRP stimulate IL-6 and TNF-? secretion in keratinocytes, 3) that SP activated all three MAPK families and the NF?B transcriptional signaling pathway in keratinocytes, and 4) that SP and CGRP stimulated inflammatory mediator production in keratinocytes is dependent on ERK1/2 and JNK activation. These studies provide evidence suggesting that disruption of ERK1/2 and JNK signaling may potentially be an effective therapy for inflammatory skin diseases and pain syndromes mediated by exaggerated sensory neuron-keratinocyte signaling. PMID:23958840

Shi, Xiaoyou; Wang, Liping; Clark, J David; Kingery, Wade S

2013-09-10

35

Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats.  

PubMed Central

Alveolar type II cell proliferation occurs after many forms of lung injury and is thought to play a critical role in alveolar epithelial repair. Keratinocyte growth factor/fibroblast growth factor 7 (KGF) has been shown to promote alveolar type II cell growth in primary culture and alveolar epithelial hyperplasia in vivo. In this study, we used immunohistochemical analysis to determine the intrapulmonary distribution and cellular localization of recombinant human KGF (rhKGF) instilled into the trachea of rats. 6 h after administration, immunoreactive KGF was observed within the lung parenchyma and along alveolar epithelial cell membranes. By 18-24 h, KGF was detected intracellularly in alveolar epithelial cells and intraalveolar macrophages. Immunoreactive KGF was not demonstrable 48 h after delivery or in lung sections from PBS-treated animals. Intratracheal instillation of 5 mg/kg rhKGF stimulated a marked, time-dependent increase in the alveolar type II cell specific labeling index to a maximum level of 33 +/- 3% 48 h after rhKGF administration compared with 1.3 +/- 0.3% after PBS instillation. In addition, this increase in type II cell proliferation in vivo was documented by flow cytometric analysis of isolated type II cells which revealed a nearly fivefold increase in the proportion of cells traversing through the S and G2/M phases of the cell cycle. To test the hypothesis that KGFs effects on type II cells in vivo might affect the response to lung injury, rats were treated with rhKGF and exposed to hyperoxia. Animals that received 1 or 5 mg/kg rhKGF exhibited dramatically reduced mortality (P < 0.001, for both doses). Survival for animals treated with 0.1 mg/kg rhKGF was not significantly different from either untreated rats or animals treated with heat-denatured rhKGF. The lungs of rhKGF-treated animals that survived hyperoxia exposure had minimal hemorrhage and no exudate within the intraalveolar space. These experiments established that intratracheal administration of rhKGF stimulated alveolar type II cell proliferation in vivo and reduced hyperoxia-induced lung injury in rats. Directed delivery of KGF to the lungs may provide a therapeutic strategy to preserve or restore the alveolar epithelium during exposure to hyperoxia or other injurious agents. Images PMID:7560096

Panos, R J; Bak, P M; Simonet, W S; Rubin, J S; Smith, L J

1995-01-01

36

Efficacy of keratinocyte growth factor (palifermin) for the treatment of caustic esophageal burns  

PubMed Central

Current treatment strategies against the development of corrosive esophageal strictures remain unsatisfactory. Thus, the aim of the present study was to investigate the efficacy of keratinocyte growth factor, in the form of palifermin, for the prevention of stricture development following esophageal caustic injuries in a rat model. A total of 32 female Wistar albino rats were divided into four groups, which included the control (C), burn (B), steroid (S) and steroid plus palifermin (S/P) groups. An experimental corrosive esophageal burn model was established in the B, S and S/P groups. Weight gain was recorded and histopathological evaluation was performed for each group. Weight gain in the S and B groups was compared with the control group and statistically significant differences were observed. In addition, statistically significant differences in weight gain were observed between the S/P group and the B group. Histopathologically, statistically significant differences were identified with regard to submucosal collagen deposition, muscularis mucosa and tunica muscularis damage when comparing the B group with the C group. In addition, statistically significant differences were observed when comparing the S and S/P groups with the B group. Furthermore, significant submucosal collagen deposition and tunica muscularis damage were observed in the S group when compared with the S/P group. The stenosis indexes in the C and S groups were significantly lower compared with the B group. In addition, the stenosis index in the S/P group was significantly lower compared with the S group. To the best of our knowledge, the present study is the first to investigate the effect of palifermin on corrosive esophageal burns. The addition of palifermin to the corrosive esophageal burn standard treatment regimen was found to reduce the degree of fibrosis and ameliorate histopathological damage in an experimental model of corrosive esophagitis in rats. PMID:25187801

NUMANO?LU, KEMAL VARIM; TATLI, DUYGU; BEKTA?, SIBEL; ER, EBUBEKIR

2014-01-01

37

Efficacy of keratinocyte growth factor (palifermin) for the treatment of caustic esophageal burns.  

PubMed

Current treatment strategies against the development of corrosive esophageal strictures remain unsatisfactory. Thus, the aim of the present study was to investigate the efficacy of keratinocyte growth factor, in the form of palifermin, for the prevention of stricture development following esophageal caustic injuries in a rat model. A total of 32 female Wistar albino rats were divided into four groups, which included the control (C), burn (B), steroid (S) and steroid plus palifermin (S/P) groups. An experimental corrosive esophageal burn model was established in the B, S and S/P groups. Weight gain was recorded and histopathological evaluation was performed for each group. Weight gain in the S and B groups was compared with the control group and statistically significant differences were observed. In addition, statistically significant differences in weight gain were observed between the S/P group and the B group. Histopathologically, statistically significant differences were identified with regard to submucosal collagen deposition, muscularis mucosa and tunica muscularis damage when comparing the B group with the C group. In addition, statistically significant differences were observed when comparing the S and S/P groups with the B group. Furthermore, significant submucosal collagen deposition and tunica muscularis damage were observed in the S group when compared with the S/P group. The stenosis indexes in the C and S groups were significantly lower compared with the B group. In addition, the stenosis index in the S/P group was significantly lower compared with the S group. To the best of our knowledge, the present study is the first to investigate the effect of palifermin on corrosive esophageal burns. The addition of palifermin to the corrosive esophageal burn standard treatment regimen was found to reduce the degree of fibrosis and ameliorate histopathological damage in an experimental model of corrosive esophagitis in rats. PMID:25187801

Numano?lu, Kemal Varim; Tatli, Duygu; Bekta?, Sibel; Er, Ebubekir

2014-10-01

38

Proliferation–differentiation relationships in the expression of heparin-binding epidermal growth factor-related factors and erbB receptors by normal and psoriatic human keratinocytes  

Microsoft Academic Search

The topological relationships between erbB receptors and ligands of the epidermal growth factor family were characterized by immunocytochemistry in normal and psoriatic epidermis and in proliferating and differentiating human keratinocytes in culture. Spatial colocalization of receptors and ligands was assessed by dual immunostaining. Expression of epidermal growth factor receptor (EGFr), erbB2, and erbB3, but not erbB4, was detected throughout the

Michael Piepkorn; Holly Predd; Robert Underwood; Paul Cook

2003-01-01

39

Keratinocyte growth factor induces gene expression signature associated with suppression of malignant phenotype of cutaneous squamous carcinoma cells.  

PubMed

Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes. PMID:22427941

Toriseva, Mervi; Ala-aho, Risto; Peltonen, Sirkku; Peltonen, Juha; Grénman, Reidar; Kähäri, Veli-Matti

2012-01-01

40

Human colon fibroblasts induce differentiation and proliferation of intestinal epithelial cells through the direct paracrine action of keratinocyte growth factor.  

PubMed

The effects exerted by the keratinocyte growth factor (KGF) on intestinal epithelial cells cultured in vitro are influenced by cell confluence and differentiation through the modulation of keratinocyte growth factor receptor (KGFR) expression. In order to better define the contribution of KGF on the intestinal epithelial cell differentiation and proliferation, here we developed a coculture model, able to mimick in vitro the epithelial-mesenchymal interactions of the bowel. In consequence of its ability to produce KGF, demonstrated by real-time PCR and Western blot analysis, the human colon fibroblast cell line CCD-18 has been selected as coculture partner for the intestinal epithelial Caco-2 cell line. Analysis of the expression of the differentiation and proliferation markers CEA and Ki67, through double immunofluorescence assays, showed that either the coculture with CCD-18 cells or the incubation with primary colon fibroblast-derived conditioned media (CM-F and CM-F2) induced an increase in differentiation and proliferation of confluent intestinal epithelial Caco-2 or HT29 cells, parallel to that obtained by KGF treatment. Use of anti-KGF blocking antibodies and of a tyrosine kinase KGFR inhibitor demonstrated the contribution of KGF and the direct role of its receptor in the regulation of epithelial growth and differentiation, indicating that KGF is a crucial paracrine factor involved in promoting these effects. PMID:19326389

Visco, Vincenzo; Bava, Felice A; d'Alessandro, Federica; Cavallini, Marco; Ziparo, Vincenzo; Torrisi, Maria Rosaria

2009-07-01

41

Keratinocyte growth factor and stem cell factor to improve thymopoiesis after autologous CD34+ cell transplantation in rhesus macaques.  

PubMed

Deficient thymopoiesis and retarded recovery of naive CD4(+) T cells are important determinants of insufficient immune-competence following hematopoietic stem cell transplantation (HSCT). Although keratinocyte growth factor (KGF) may protect the thymic epithelium, stem cell factor (SCF) is involved in early thymopoiesis. We evaluated whether KGF alone or combined with SCF would affect thymopoiesis and hematologic recovery following myeloablative autologous HSCT into rhesus macaques. Purpose-bred adult rhesus macaques received 10(6) autologous CD34(+)-selected mononuclear bone marrow cells (BMC)/kg after 9 Gy myeloablative conditioning. Animals were treated with phosphate-buffered saline (PBS) (n = 2), KGF alone (n = 2), or KGF combined with SCF (n = 2). KGF-treated animals showed accelerated hematologic recovery, improved thymopoiesis, and enhanced naive T-cell recovery following transplantation. Improved T cell recovery was not associated with protection against cytomegalovirus reactivation nor with improved antibody response to tetanus toxoid vaccination. Animals treated with KGF and SCF experienced severe adverse events that precluded evaluation of thymopoiesis and T cell recovery. Collectively, our data confirm that KGF may enhance thymopoiesis. PMID:21963880

Wils, Evert-Jan; Aerts-Kaya, Fatima S F; Rombouts, Elwin J C; van Mourik, Irene; Rijken-Schelen, Anita; Visser, Trudi P; Braakman, Eric; Wagemaker, Gerard; Cornelissen, Jan J

2012-01-01

42

Requirement of G?i1/3-Gab1 signaling complex for keratinocyte growth factor-induced PI3K-AKT-mTORC1 activation.  

PubMed

Keratinocyte growth factor (KGF), also termed as fibroblast growth factor-7, promotes proliferation, migration, and adhesion of skin keratinocytes via binding to keratinocyte growth factor receptor (KGFR) and subsequent activation of downstream signaling including the PI3K-AKT-mTORC1 pathway. Here, we found that the ?-subunits of the G proteins (G?i1/3) and growth factor receptor binding 2-associated binding protein 1 (Gab1) are required for this activation process. With KGF stimulation, G?i1/3 formed a complex with KGFR and was required for subsequent Gab1 recruitment, phosphorylation, and following PI3K-p85 activation. In addition, G?i1/3 short hairpin RNA knockdown largely inhibited KGF-induced cell proliferation, migration, and the accumulation of cyclin D1/fibronectin in cultured skin keratinocytes. Furthermore, we observed increased expression of G?i1/3 in wounded human skin and keloid skin tissues, suggesting the possible involvement of G?i1/3 in wound healing and keloid formation. Overall, we suggest that G?i1/3 proteins lie downstream of KGFR, but upstream of Gab1-mediated activation of PI3K-AKT-mTORC1 signaling, thus revealing a role for G?i proteins in mediating KGFR signaling, cell migration, and possible wound healing. PMID:25078664

Zhang, Yi-ming; Zhang, Zhi-qing; Liu, Yuan-yuan; Zhou, Xin; Shi, Xiao-hua; Jiang, Qin; Fan, Dong-li; Cao, Cong

2015-01-01

43

A decisive function of transforming growth factor-?/Smad signaling in tissue morphogenesis and differentiation of human HaCaT keratinocytes  

PubMed Central

?The mechanism by which transforming growth factor-? (TGF?) regulates differentiation in human epidermal keratinocytes is still poorly understood. To assess the role of Smad signaling, we engineered human HaCaT keratinocytes either expressing small interfering RNA against Smads2, 3, and 4 or overexpressing Smad7 and verified impaired Smad signaling as decreased Smad phosphorylation, aberrant nuclear translocation, and altered target gene expression. Besides abrogation of TGF?-dependent growth inhibition in conventional cultures, epidermal morphogenesis and differentiation in organotypic cultures were disturbed, resulting in altered tissue homeostasis with suprabasal proliferation and hyperplasia upon TGF? treatment. Neutralizing antibodies against TGF?, similar to blocking the actions of EGF-receptor or keratinocyte growth factor, caused significant growth reduction of Smad7-overexpressing cells, thereby demonstrating that epithelial hyperplasia was attributed to TGF?-induced “dermis”-derived growth promoting factors. Furthermore impaired Smad signaling not only blocked the epidermal differentiation process or caused epidermal-to-mesenchymal transition but induced a switch to a complex alternative differentiation program, best characterized as mucous/intestinal-type epithelial differentiation. As the same alternative phenotype evolved from both modes of Smad-pathway interference, and reduction of Smad7-overexpression caused reversion to epidermal differentiation, our data suggest that functional TGF?/Smad signaling, besides regulating epidermal tissue homeostasis, is not only essential for terminal epidermal differentiation but crucial in programming different epithelial differentiation routes. PMID:21289094

Buschke, Susanne; Stark, Hans-Jürgen; Cerezo, Ana; Prätzel-Wunder, Silke; Boehnke, Karsten; Kollar, Jasmin; Langbein, Lutz; Heldin, Carl-Henrik; Boukamp, Petra

2011-01-01

44

Selective expansion of the beta-cell compartment in the pancreas of keratinocyte growth factor transgenic mice.  

PubMed

Epithelial-mesenchymal interactions are essential for growth, differentiation, and regeneration of exocrine and endocrine cells in the pancreas. The keratinocyte growth factor (KGF) is derived from mesenchyme and has been shown to promote epithelial cell differentiation and proliferation in a paracrine fashion. Here, we have examined the effect of ectopic expression of KGF on pancreatic differentiation and proliferation in transgenic mice by using the proximal elastase promoter. KGF transgenic mice were generated following standard procedures and analyzed by histology, morphometry, immunohistochemistry, Western blot analysis, and glucose tolerance testing. In KGF transgenic mice, the number of islets, the average size of islets, and the relation of endocrine to exocrine tissue are increased compared with littermate controls. An expansion of the beta-cell population is responsible for the increase in the endocrine compartment. Ectopic expression of KGF results in proliferation of beta-cells and pancreatic duct cells most likely through activation of the protein kinase B (PKB)/Akt signaling pathway. Glucose tolerance and insulin secretion are impaired in transgenic animals. These results provide evidence that ectopic expression of KGF in acinar cells promotes the expansion of the beta-cell lineage in vivo through activation of the PKB/Akt pathway. Furthermore, the observed phenotype demonstrates that an increase in the beta-cell compartment does not necessarily result in an improved glucose tolerance in vivo. PMID:18372394

Wagner, Martin; Koschnick, Stefan; Beilke, Sven; Frey, Melanie; Adler, Guido; Schmid, Roland M

2008-05-01

45

Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound  

PubMed Central

Keratinocyte growth factor (KGF) is a potent mitogen for epithelial cells, and it promotes survival of these cells under stress conditions. In a search for KGF-regulated genes in keratinocytes, we identified the gene encoding the transcription factor NF-E2-related factor 2 (Nrf2). Nrf2 is a key player in the cellular stress response. This might be of particular importance during wound healing, where large amounts of reactive oxygen species are produced as a defense against invading bacteria. Therefore, we studied the wound repair process in Nrf2 knockout mice. Interestingly, the expression of various key players involved in wound healing was significantly reduced in early wounds of the Nrf2 knockout animals, and the late phase of repair was characterized by prolonged inflammation. However, these differences in gene expression were not reflected by obvious histological abnormalities. The normal healing rate appears to be at least partially due to an up-regulation of the related transcription factor Nrf3, which was also identified as a target of KGF and which was coexpressed with Nrf2 in the healing skin wound. Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair. PMID:12101242

Braun, Susanne; Hanselmann, Christine; Gassmann, Marcus G.; auf dem Keller, Ulrich; Born-Berclaz, Christiane; Chan, Kaimin; Wai Kan, Yuet; Werner, Sabine

2002-01-01

46

Bronchoalveolar Sublineage Specification of Pluripotent Stem Cells: Effect of Dexamethasone Plus cAMP-Elevating Agents and Keratinocyte Growth Factor.  

PubMed

Respiratory progenitors can be efficiently generated from pluripotent stem cells (PSCs). However, further targeted differentiation into bronchoalveolar sublineages is still in its infancy, and distinct specifying effects of key differentiation factors are not well explored. Focusing on airway epithelial Clara cell generation, we analyzed the effect of the glucocorticoid dexamethasone plus cAMP-elevating agents (DCI) on the differentiation of murine embryonic and induced pluripotent stem cells (iPSCs) into bronchoalveolar epithelial lineages, and whether keratinocyte growth factor (KGF) might further influence lineage decisions. We demonstrate that DCI strongly induce expression of the Clara cell marker Clara cell secretory protein (CCSP). While KGF synergistically supports the inducing effect of DCI on alveolar markers with increased expression of surfactant protein (SP)-C and SP-B, an inhibitory effect on CCSP expression was shown. In contrast, neither KGF nor DCI seem to have an inducing effect on ciliated cell markers. Furthermore, the use of iPSCs from transgenic mice with CCSP promoter-dependent lacZ expression or a knockin of a YFP reporter cassette in the CCSP locus enabled detection of derivatives with Clara cell typical features. Collectively, DCI was shown to support bronchoalveolar specification of mouse PSCs, in particular Clara-like cells, and KGF to inhibit bronchial epithelial differentiation. The targeted in vitro generation of Clara cells with their important function in airway protection and regeneration will enable the evaluation of innovative cellular therapies in animal models of lung diseases. PMID:25316003

Katsirntaki, Katherina; Mauritz, Christina; Olmer, Ruth; Schmeckebier, Sabrina; Sgodda, Malte; Puppe, Verena; Eggenschwiler, Reto; Duerr, Julia; Schubert, Susanne C; Schmiedl, Andreas; Ochs, Matthias; Cantz, Tobias; Salwig, Isabelle; Szibor, Marten; Braun, Thomas; Rathert, Christian; Martens, Andreas; Mall, Marcus A; Martin, Ulrich

2015-02-01

47

Differential induction of phosphatidylcholine hydrolysis, diacylglycerol formation and protein kinase C activation by epidermal growth factor and transforming growth factor-alpha in normal human skin fibroblasts and keratinocytes.  

PubMed Central

We have investigated coupling between the epidermal growth factor (EGF) receptor and the phospholipase C (PLC)/protein kinase C (PKC) signal-transduction system in normal skin fibroblasts and keratinocytes, for which EGF and transforming growth factor alpha (TGF-alpha) are mitogenic. EGF and TGF-alpha induced a rapid increase in tyrosine phosphorylation of the EGF receptor, in both fibroblasts and keratinocytes, but failed to induce tyrosine phosphorylation of PLC-gamma 1 or detectable phosphoinositide hydrolysis, as measured by two sensitive assays. In fibroblasts, EGF induced phosphatidylcholine (PC) hydrolysis, resulting in increased diacylglycerol (DAG). In contrast, in keratinocytes, there was no detectable PC hydrolysis or elevation of DAG in response to EGF or TGF-alpha. EGF and TGF-alpha activated PKC in fibroblasts, as evidenced by increased phosphorylation of a specific cellular PKC substrate (myristoylated alanine-rich C-kinase substrate, 'MARCKS'). In keratinocytes, TGF-alpha and EGF induced only a modest increase in MARCKS protein phosphorylation. This apparent modest activation of PKC, in the absence of detectable DAG formation, may have been mediated by arachidonic acid, which was released from keratinocytes in response to TGF-alpha, and has been shown to stimulate PKC activity in vitro. These data demonstrate that (1) in dermal fibroblasts and keratinocytes, which express normal levels of EGF receptors, EGF receptor activation is not coupled to tyrosine phosphorylation of PLC-gamma 1 or PtdIns hydrolysis, suggesting that these events are not required for the mitogenic activity of EGF or TGF-alpha in these cells, (2) coupling of EGF receptor to PC hydrolysis is cell-type specific, and (3) in skin fibroblasts, DAG, formed through EGF-induced PC hydrolysis, is capable of activating PKC. Images Figure 3 Figure 4 Figure 6 PMID:7690546

Reynolds, N J; Talwar, H S; Baldassare, J J; Henderson, P A; Elder, J T; Voorhees, J J; Fisher, G J

1993-01-01

48

Long-Term Maintenance of Limbal Epithelial Progenitor Cells Using Rho Kinase Inhibitor and Keratinocyte Growth Factor  

PubMed Central

Corneal epithelial stem cells are located in the limbus, the junction between the cornea and the conjunctiva. A limbal epithelium model in vitro would be useful for the study of epithelial stem cells, as well as improving the quality of cultivated epithelial sheets for the treatment of limbal stem cell deficiency. In this study, we succeeded in constructing a limbal epithelium-like structure that could be maintained for at least 5 months in vitro. We modified conventional medium by replacing epidermal growth factor with keratinocyte growth factor (KGF) and adding Y-27632, a rho kinase inhibitor. Using this medium, epithelial cells freshly isolated from human limbus were cocultured with human mesenchymal stem cell-derived feeder cells. Cells formed a stratified layer without air exposure, and both basal and suprabasal layers maintained their unique morphologies for up to 5 months. Basal layers expressed the progenitor marker p63 uniformly and K15 heterogeneously. Expressions of PAX6, K3, and K12 indicated that cell sheets underwent normal differentiation in the corneal epithelium lineage. Although medium was changed daily after day 7, cell debris was observed every day, suggesting that cell sheets underwent turnover. Furthermore, secondary colonies were observed from cells dissociated from 1-month and 3-month cultured sheets. In conclusion, human limbal epithelial cell sheet cultures with KGF and Y-27632 maintained stratification, high expression of both stem/progenitor markers and differentiation markers, and colony-forming cells long-term. This protocol may be useful as an in vitro limbal epithelial model for basic studies. PMID:23981725

Miyashita, Hideyuki; Yokoo, Seiichi; Yoshida, Satoru; Kawakita, Tetsuya; Yamagami, Satoru; Tsubota, Kazuo

2013-01-01

49

?-Adducin siRNA disruption of the spectrin-based cytoskeleton in differentiating keratinocytes prevented by calcium acting through calmodulin/epidermal growth factor receptor/cadherin pathway.  

PubMed

Here, we report that siRNA transfection of ?-adducin significantly disrupted the spectrin-based cytoskeleton and cytoskeletal arrangements of both ?-adducin and PKC? by substantially inhibiting the expression of ?-adducin, spectrin and PKC? proteins in differentiating keratinocytes. However, extracellular Ca2+ treatment blocked the inhibitory effects of the ?-adducin siRNA. Ca2+ also prevented the significant down-regulation of two differentiation markers involucrin and K1/10 and the distinct up-regulation of proliferation marker K14 in ?-adducin siRNA transfected keratinocytes. In addition, ?-adducin knockdown resulted in a substantial reduction of epidermal growth factor receptor (EGFR), cadherin and ?-catenin and enhanced phosphorylation of EGFR on tyrosine 1173 and Ca2+ prevented these changes. Furthermore, Ca2+ blocked the inhibitory effects of ?-adducin siRNA on the expression of calmodulin, phosphorylated-calmodulin (P-CaM((Tyr138))) and myristoylated alanine-rich C-kinase substrate (MARCKS) in keratinocytes. Co-immunoprecipitation studies further revealed that calmodulin, not MARCKS, strongly interacted with EGFR, cadherin and ?-catenin. Our data suggest that Ca2+ plays an important role in regulating the expression and function of ?-adducin to sustain normal organization of the spectrin-based cytoskeleton and the differentiation properties in keratinocytes through the calmodulin/EGFR/cadherin signaling pathway. PMID:25305142

Wu, Jianghong; Masci, Paul P; Chen, Chenfeng; Chen, Jiezhong; Lavin, Martin F; Zhao, Kong-Nan

2015-01-01

50

Dermal fibroblast-derived growth factors restore the ability of beta(1) integrin-deficient embryonal stem cells to differentiate into keratinocytes.  

PubMed

Embryonal stem (ES) cells that are homozygous null for the beta(1) integrin subunit fail to differentiate into keratinocytes in vitro but do differentiate in teratomas and wild-type/beta(1)-null chimeric mice. The failure of beta(1)-null ES cells to differentiate in culture might be the result of defective extracellular matrix assembly or reduced sensitivity to soluble inducing factors. By culturing embryoid bodies on dead, deepidermized human dermis (DED) we showed that epidermal basement membrane did not induce beta(1)-null ES cells to undergo keratinocyte differentiation and did not stimulate the differentiation of wild-type ES cells. Coculture with epidermal keratinocytes also had no effect. However, when human dermal fibroblasts were incorporated into DED, the number of epidermal cysts formed by wild-type ES cells increased dramatically, and small groups of keratin 14-positive cells differentiated from beta(1)-null ES cells. Fibroblast-conditioned medium stimulated differentiation of K14-positive cells in wild-type and beta(1)-null embryoid bodies. Of a range of growth factors tested, KGF, FGF10, and TGFalpha all stimulated differentiation of keratin 14-positive beta(1)-null cells, and KGF and FGF10 were shown to be produced by the fibroblasts used in coculture experiments. The effects of the growth factors on wild-type ES cells were much less pronounced, suggesting that the concentrations of inducing factors already present in the medium were not limiting for wild-type cells. We conclude that the lack of beta(1) integrins decreases the sensitivity of ES cells to soluble factors that induce keratinocyte differentiation. PMID:11237462

Bagutti, C; Hutter, C; Chiquet-Ehrismann, R; Fässler, R; Watt, F M

2001-03-15

51

Regulation of Bcl-xL expression in human keratinocytes by cell–substratum adhesion and the epidermal growth factor?receptor  

PubMed Central

Cell–substratum adhesion is an essential requirement for survival of human neonatal keratinocytes in vitro. Similarly, activation of the epidermal growth factor receptor (EGF-R) has recently been implicated not only in cell cycle progression but also in survival of normal keratinocytes. The mechanisms by which either cell–substratum adhesion or EGF-R activation protect keratinocytes from programmed cell death are poorly understood. Here we describe that blockade of the EGF-R and inhibition of substratum adhesion share a common downstream event, the down-regulation of the cell death protector Bcl-xL. Expression of Bcl-xL protein was down-regulated during forced suspension culture of keratinocytes, concurrent with large-scale apoptosis. Similarly, EGF-R blockade was accompanied by down-regulation of Bcl-xL steady-state mRNA and protein levels to an extent comparable to that observed in forced suspension culture. However, down-regulation of Bcl-xL expression by EGF-R blockade was not accompanied by apoptosis; in this case, a second signal, generated by passaging, was required to induce rapid and large-scale apoptosis. These findings are consistent with the conclusions that (i) Bcl-xL represents a shared molecular target for signaling through cell-substrate adhesion receptors and the EGF-R, and (ii) reduced levels of Bcl-xL expression through EGF-R blockade lower the tolerance of keratinocytes for cell death signals generated by cellular stress. PMID:9144191

Rodeck, Ulrich; Jost, Monika; DuHadaway, James; Kari, Csaba; Jensen, Pamela J.; Risse, Barbara; Ewert, Donald L.

1997-01-01

52

Keratinocyte growth factor prevents radiation damage to salivary glands by expansion of the stem/progenitor pool.  

PubMed

Irradiation of salivary glands during radiotherapy treatment of patients with head and neck cancer evokes persistent hyposalivation. This results from depletion of stem cells, which renders the gland incapable of replenishing saliva to produce acinar cells. The aim of this study was to investigate whether it is possible to expand the salivary gland stem/progenitor cell population, thereby preventing acinar cell depletion and subsequent gland dysfunction after irradiation. To induce cell proliferation, keratinocyte growth factor (DeltaN23-KGF, palifermin) was administered to C57BL/6 mice for 4 days before and/or after local irradiation of salivary glands. Salivary gland vitality was quantified by in vivo saliva flow rates, morphological measurements, and a newly developed in vitro salisphere progenitor/stem cell assay. Irradiation of salivary glands led to a pronounced reduction in the stem cells of the tissues, resulting in severe hyposalivation and a reduced number of acinar cells. DeltaN23-KGF treatment for 4 days before irradiation indeed induced salivary gland stem/progenitor cell proliferation, increasing the stem and progenitor cell pool. This did not change the relative radiation sensitivity of the stem/progenitor cells, but, as a consequence, an absolute higher number of stem/progenitor cells and acinar cells survived after radiation. Postirradiation treatment with DeltaN23-KGF also improved gland function, and this effect was much more pronounced in DeltaN23-KGF pretreated animals. Post-treatment with DeltaN23-KGF seemed to act through accelerated expansion of the pool of progenitor/stem cells that survived the irradiation treatment. Overall, our data indicate that DeltaN23-KGF is a promising drug to enhance the number of salivary gland progenitor/stem cells and consequently prevent radiation-induced hyposalivation. Disclosure of potential conflicts of interest is found at the end of this article. PMID:18669914

Lombaert, Isabelle M A; Brunsting, Jeanette F; Wierenga, Pieter K; Kampinga, Harm H; de Haan, Gerald; Coppes, Robert P

2008-10-01

53

Reduction of radiochemotherapy-induced early oral mucositis by recombinant human keratinocyte growth factor (palifermin): Experimental studies in mice  

SciTech Connect

Purpose: To study the effect of recombinant human keratinocyte growth factor (rHuKGF or palifermin) on oral mucositis induced by radiochemotherapy in a mouse model. Methods and Materials: Cis-diamminedichloroplatinum (cisplatin) and/or 5-fluorouracil were given before single dose irradiation, combined with palifermin before or after the treatment, or both. Daily fractionated irradiation for 2 weeks was followed by graded test doses. With additional chemotherapy in Week 1, palifermin was given before radiotherapy and at the end of the first week, or additionally at the end of Week 2. Radiochemotherapy in Week 2 was combined with palifermin at the end of Weeks 1 and 2, Weeks 1, 2, and 3, or additionally before radiotherapy. Ulceration of mouse tongue mucosa was analyzed as the endpoint. Results: The dose associated with ulcer induction in 50% of the mice (ED{sub 50}) for single-dose irradiation was 11.5 {+-} 0.7 Gy. Palifermin increased the ED{sub 50} to about 19 Gy in all protocols tested. Similar values were observed when chemotherapy was added before irradiation. With fractionated irradiation, palifermin increased the ED{sub 50} for test irradiation from 5.7 {+-} 1.5 Gy to 12-15 Gy, depending on the administration protocol. With chemotherapy in Week 1, two palifermin injections had no significant effect, but a third injection increased the ED{sub 50} to 13 Gy. With chemotherapy in Week 2, all palifermin protocols resulted in ED{sub 50} values of 13-14 Gy. Conclusion: A marked increase in oral mucosal radiation tolerance by palifermin was found, which was preserved in combinations with chemotherapy using cisplatin and/or 5-fluorouracil.

Doerr, Wolfgang [Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany) and Experimentelles Zentrum, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany)]. E-mail: doerr@rcs.urz.tu-dresden.de; Baessler, Stefan; Reichel, Sandra [Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany); Spekl, Kathrin [Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany); Experimentelles Zentrum, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany)

2005-07-01

54

Interferon regulatory factor 6 regulates keratinocyte migration.  

PubMed

Interferon regulatory factor 6 (Irf6) regulates keratinocyte proliferation and differentiation. In this study, we tested the hypothesis that Irf6 regulates cellular migration and adhesion. Irf6-deficient embryos at 10.5?days post-conception failed to close their wound compared with wild-type embryos. In vitro, Irf6-deficient murine embryonic keratinocytes were delayed in closing a scratch wound. Live imaging of the scratch showed deficient directional migration and reduced speed in cells lacking Irf6. To understand the underlying molecular mechanisms, cell-cell and cell-matrix adhesions were investigated. We show that wild-type and Irf6-deficient keratinocytes adhere similarly to all matrices after 60?min. However, Irf6-deficient keratinocytes were consistently larger and more spread, a phenotype that persisted during the scratch-healing process. Interestingly, Irf6-deficient keratinocytes exhibited an increased network of stress fibers and active RhoA compared with that observed in wild-type keratinocytes. Blocking ROCK, a downstream effector of RhoA, rescued the delay in closing scratch wounds. The expression of Arhgap29, a Rho GTPase-activating protein, was reduced in Irf6-deficient keratinocytes. Taken together, these data suggest that Irf6 functions through the RhoA pathway to regulate cellular migration. PMID:24777480

Biggs, Leah C; Naridze, Rachelle L; DeMali, Kris A; Lusche, Daniel F; Kuhl, Spencer; Soll, David R; Schutte, Brian C; Dunnwald, Martine

2014-07-01

55

The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats  

SciTech Connect

Purpose: Radiation-induced lung toxicity is a significant dose-limiting side effect of radiotherapy for thoracic tumors. Recombinant human keratinocyte growth factor (rHuKGF) has been shown to be a mitogen for type II pneumocytes. The purpose of this study was to determine whether rHuKGF prevents or ameliorates the severity of late lung damage from fractionated irradiation in a rat model. Methods and materials: Female Fisher 344 rats were irradiated to the right hemithorax with a dose of 40 Gy/5 fractions/5 days. rHuKGF at dose of 5 mg/kg or 15 mg/kg was given via a single intravenous injection 10 min after the last fraction of irradiation. Animals were followed for 6 months after irradiation. Results: The breathing rate increased beginning at 6 weeks and reached a peak at 14 weeks after irradiation. The average breathing frequencies in the irradiated groups with rHuKGF (5 mg/kg and 15 mg/kg) treatment were significantly lower than that in the group receiving radiation without rHuKGF (116.5 {+-} 1.0 and 115.2 {+-} 0.8 vs 123.5 {+-} 1.2 breaths/min, p < 0.01). The severity of lung fibrosis and the level of immunoreactivity of integrin {alpha}v{beta}6, TGF{beta}1, type II TGF{beta} receptor, Smad3, and phosphorylated Smad2/3 were significantly decreased only in the group receiving irradiation plus high-dose rHuKGF treatment compared with irradiation plus vehicle group, suggesting a dose response for the effect of rHuKGF. Conclusions: This study is the first to demonstrate that rHuKGF treatment immediately after irradiation protects against late radiation-induced pulmonary toxicity. These results suggest that restoration of the integrity of the pulmonary epithelium via rHuKGF stimulation may downregulate the TGF-{beta}-mediated fibrosis pathway. These data also support the use of rHuKGF in a clinical trial designed to prevent radiation-induced lung injury.

Chen Liguang [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Brizel, David M. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Rabbani, Zahid N. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Samulski, Thaddeus V. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Farrell, Catherine L. [Amgen, Inc., Thousand Oaks, CA (United States); Larrier, Nicole [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Anscher, Mitchell S. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Vujaskovic, Zeljko [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)]. E-mail: vujas@radonc.duke.edu

2004-12-01

56

Keratinocyte Growth Factor Administration Attenuates Murine Pulmonary Mycobacterium tuberculosis Infection through Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF)-dependent Macrophage Activation and Phagolysosome Fusion.  

PubMed

Augmentation of innate immune defenses is an appealing adjunctive strategy for treatment of pulmonary Mycobacterium tuberculosis infections, especially those caused by drug-resistant strains. The effect of intranasal administration of keratinocyte growth factor (KGF), an epithelial mitogen and differentiation factor, on M. tuberculosis infection in mice was tested in prophylaxis, treatment, and rescue scenarios. Infection of C57BL6 mice with M. tuberculosis resulted in inoculum size-dependent weight loss and mortality. A single dose of KGF given 1 day prior to infection with 10(5) M. tuberculosis bacilli prevented weight loss and enhanced pulmonary mycobacterial clearance (compared with saline-pretreated mice) for up to 28 days. Similar effects were seen when KGF was delivered intranasally every third day for 15 days, but weight loss and bacillary growth resumed when KGF was withdrawn. For mice with a well established M. tuberculosis infection, KGF given every 3 days beginning on day 15 postinoculation was associated with reversal of weight loss and an increase in M. tuberculosis clearance. In in vitro co-culture experiments, M. tuberculosis-infected macrophages exposed to conditioned medium from KGF-treated alveolar type II cell (MLE-15) monolayers exhibited enhanced GM-CSF-dependent killing through mechanisms that included promotion of phagolysosome fusion and induction of nitric oxide. Alveolar macrophages from KGF-treated mice also exhibited enhanced GM-CSF-dependent phagolysosomal fusion. These results provide evidence that administration of KGF promotes M. tuberculosis clearance through GM-CSF-dependent mechanisms and enhances host defense against M. tuberculosis infection. PMID:25605711

Pasula, Rajamouli; Azad, Abul K; Gardner, Jason C; Schlesinger, Larry S; McCormack, Francis X

2015-03-13

57

Effect of a Vitamin D3 Analogue on Keratinocyte Growth Factor-Induced Cell Proliferation in Benign Prostate Hyperplasia  

Microsoft Academic Search

Prostate enlargement and function is under the dual control of androgens and intraprostatic growth factors. They regulate, in con- cert, prostate cell proliferation and apoptosis. An increased signaling of both growth factors and androgens are supposed to underlie benign prostate hyperplasia (BPH), one of the more common disorders of the aging male. Since, in clinical practice, androgen ablation resulted in

CLARA CRESCIOLI; MARIO MAGGI; GABRIELLA BARBARA VANNELLI; MICHAELA LUCONI; ROBERTO SALERNO; TULLIO BARNI; MASSIMO GULISANO; GIANNI FORTI; MARIO SERIO

2010-01-01

58

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

SciTech Connect

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.

Gao, Lin; Chao, Lee [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)] [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States); Chao, Julie, E-mail: chaoj@musc.edu [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)] [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)

2010-02-01

59

Growth Factors, Cell Adhesion and Matrix | ABSTRACTS A differential response between normal and psoriatic keratinocytes' N-methyl-D-aspartate  

E-print Network

of wound healing in psoriasis. 874 Dysregulated iRHOM2/ADAM17 inTylosis with oesophageal cancer affects assays, particularly in the absence of exogenous EGF. This led us to investigate the role of ADAM17 (TACE), whose maturation is regulated by iRhom2. Western blotting of ADAM17 in TOC keratinocytes demonstrated

Cai, Long

60

Activated Protein C Enhances Human Keratinocyte Barrier Integrity via Sequential Activation of Epidermal Growth Factor Receptor and Tie2*  

PubMed Central

Keratinocytes play a critical role in maintaining epidermal barrier function. Activated protein C (APC), a natural anticoagulant with anti-inflammatory and endothelial barrier protective properties, significantly increased the barrier impedance of keratinocyte monolayers, measured by electric cell substrate impedance sensing and FITC-dextran flux. In response to APC, Tie2, a tyrosine kinase receptor, was rapidly activated within 30 min, and relocated to cell-cell contacts. APC also increased junction proteins zona occludens, claudin-1 and VE-cadherin. Inhibition of Tie2 by its peptide inhibitor or small interfering RNA abolished the barrier protective effect of APC. Interestingly, APC did not activate Tie2 through its major ligand, angiopoietin-1, but instead acted by binding to endothelial protein C receptor, cleaving protease-activated receptor-1 and transactivating EGF receptor. Furthermore, when activation of Akt, but not ERK, was inhibited, the barrier protective effect of APC on keratinocytes was abolished. Thus, APC activates Tie2, via a mechanism requiring, in sequential order, the receptors, endothelial protein C receptor, protease-activated receptor-1, and EGF receptor, which selectively enhances the PI3K/Akt signaling to enhance junctional complexes and reduce keratinocyte permeability. PMID:21173154

Xue, Meilang; Chow, Shu-Oi; Dervish, Suat; Chan, Yee-Ka Agnes; Julovi, Sohel M.; Jackson, Christopher J.

2011-01-01

61

The Growth and Structure of Human Oral Keratinocytes in Culture  

Microsoft Academic Search

Human keratinocytes derived from explants of check (buccal) mucosa grow vigorously in culture and can be sub-cultivated twice. The structure of the oral keratinocytes in vitro is the same in primary cultures and subcultures. The cells stratify, are characterized by well-developed tonofibrillar-desmosomal complexes, and rarely exhibit signs of terminal differentiation. Unique features of the culture system that favor keratinocyte growth

Dorthe Arenholt-Bindslev; Arne Jepsen; Donald K. MacCallum; John H. Lillie

1987-01-01

62

Storage stability of keratinocyte growth factor-2 in lyophilized formulations: effects of formulation physical properties and protein fraction at the solid-air interface.  

PubMed

Lyophilized formulations of keratinocyte growth factor-2 (KGF-2) were prepared with a range of disaccharide (sucrose or trehalose) and hydroxyethyl starch (HES) mass ratios. Protein degradation was assessed as a function of time of storage of the dried formulations at 40, 50 and 60°C. Lyophilized and stored samples were rehydrated, and protein degradation was quantified by measuring loss of monomeric protein with size exclusion chromatography and by determining chemical degradation in the soluble fraction with reverse-phase chromatography. The secondary structure of the protein in the lyophilized formulations was studied with infrared spectroscopy. The magnitudes of degradation were compared the key physical properties of the formulations including retention of protein native secondary structure, glass transition temperature (Tg), inverse mean square displacements ?u(2)?(-1) for hydrogen atoms (fast ? relaxation), and the relaxation time ?(?), which correlates with relaxation due to fast Johari-Goldstein motions in the glass (Xu et al., 2013) [1]. In addition, specific surface areas of the lyophilized formulations were determined by Brunauer-Emmet-Teller analysis of krypton adsorption isotherms and used to estimate the fraction of the KGF-2 molecules residing at the solid-air interface. KGF-2 degradation rates were highest in formulations wherein the protein's structure was most perturbed, and wherein ? relaxations were fastest, but the dominant factor governing KGF-2 degradation in freeze-dried formulations was the fraction of the protein found at the glass solid-air interface. PMID:24859390

Devineni, Dilip; Gonschorek, Christoph; Cicerone, Marcus T; Xu, Yemin; Carpenter, John F; Randolph, Theodore W

2014-10-01

63

Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation.  

PubMed

Myeloablative conditioning before bone marrow transplantation (BMT) results in thymic epithelial cell (TEC) injury, T-cell immune deficiency, and susceptibility to opportunistic infections. Conditioning regimen-induced TEC damage directly contributes to slow thymopoietic recovery after BMT. Keratinocyte growth factor (KGF) is a TEC mitogen that stimulates proliferation and, when given before conditioning, reduces TEC injury. Some TEC subsets are refractory to KGF and functional T-cell responses are not fully restored in KGF-treated BM transplant recipients. Therefore, we investigated whether the addition of a pharmacologic inhibitor, PFT-beta, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs. Combined before BMT KGF + PFT-beta administration additively restored numbers of cortical and medullary TECs and improved thymic function after BMT, resulting in higher numbers of donor-derived, naive peripheral CD4(+) and CD8(+) T cells. Radiation conditioning caused a loss of T-cell zone fibroblastic reticular cells (FRCs) and CCL21 expression in lymphoid stroma. KGF + PFT-beta treatment restored both FRC and CCL21 expression, findings that correlated with improved T-cell reconstitution and an enhanced immune response against Listeria monocytogenes infection. Thus, transient p53 inhibition combined with KGF represents a novel and potentially translatable approach to promote rapid and durable thymic and peripheral T-cell recovery after BMT. PMID:19965631

Kelly, Ryan M; Goren, Emily M; Taylor, Patricia A; Mueller, Scott N; Stefanski, Heather E; Osborn, Mark J; Scott, Hamish S; Komarova, Elena A; Gudkov, Andrei V; Holländer, Georg A; Blazar, Bruce R

2010-02-01

64

Purification and growth of melanocortin 1 receptor (Mc1r)-defective primary murine melanocytes is dependent on stem cell factor from keratinocyte-conditioned media  

PubMed Central

Summary The melanocortin 1 receptor (MC1R) is a transmembrane Gs-coupled surface protein found on melanocytes that binds melanocyte stimulating hormone (MSH) and mediates activation of adenylyl cyclase and generation of the second messenger cAMP. MC1R regulates growth and differentiation of melanocytes and protects against carcinogenesis. Persons with loss-of-function polymorphisms of MC1R tend to be UV-sensitive (fair-skinned and with a poor tanning response) and are at high risk for melanoma. Mechanistic studies of the role of MC1R in melanocytic UV responses, however, have been hindered in part because Mc1r-defective primary murine melanocytes have been difficult to culture in vitro. Until now, effective growth of murine melanocytes has depended on cAMP stimulation with adenylyl cyclase activating or phosphodiesterase inhibiting agents. However, rescuing cAMP in the setting of defective MC1R signaling would be expected to confound experiments directly testing MC1R function on melanocytic UV responses. Here we report a novel method of culturing primary murine melanocytes in the absence of pharmacologic cAMP stimulation by incorporating conditioned supernatants containing stem cell factor (SCF) derived from primary keratinocytes. Importantly, this method seems to permit similar pigment expression by cultured melanocytes as that found in the skin of their parental murine strains. This novel approach will allow mechanistic investigation into MC1R’s role in protection against UV-mediated carcinogenesis and determination of the role of melanin pigment subtypes on UV-mediated melanocyte responses. PMID:19633898

Scott, Timothy L.; Wakamatsu, Kazumasa; Ito, Shosuke; D’Orazio, John A.

2015-01-01

65

A Novel Solid-Phase Site-Specific PEGylation Enhances the In Vitro and In Vivo Biostabilty of Recombinant Human Keratinocyte Growth Factor 1  

PubMed Central

Keratinocyte growth factor 1 (KGF-1) has proven useful in the treatment of pathologies associated with dermal adnexae, liver, lung, and the gastrointestinal tract diseases. However, poor stability and short plasma half-life of the protein have restricted its therapeutic applications. While it is possible to improve the stability and extend the circulating half-life of recombinant human KGF-1 (rhKGF-1) using solution-phase PEGylation, such preparations have heterogeneous structures and often low specific activities due to multiple and/or uncontrolled PEGylation. In the present study, a novel solid-phase PEGylation strategy was employed to produce homogenous mono-PEGylated rhKGF-1. RhKGF-1 protein was immobilized on a Heparin-Sepharose column and then a site-selective PEGylation reaction was carried out by a reductive alkylation at the N-terminal amino acid of the protein. The mono-PEGylated rhKGF-1, which accounted for over 40% of the total rhKGF-1 used in the PEGylation reaction, was purified to homogeneity by SP Sepharose ion-exchange chromatography. Our biophysical and biochemical studies demonstrated that the solid-phase PEGylation significantly enhanced the in vitro and in vivo biostability without affecting the over all structure of the protein. Furthermore, pharmacokinetic analysis showed that modified rhKGF-1 had considerably longer plasma half-life than its intact counterpart. Our cell-based analysis showed that, similar to rhKGF-1, PEGylated rhKGF-1 induced proliferation in NIH 3T3 cells through the activation of MAPK/Erk pathway. Notably, PEGylated rhKGF-1 exhibited a greater hepatoprotection against CCl4-induced injury in rats compared to rhKGF-1. PMID:22574160

Zhang, Jingui; Zhang, Yi; Zhang, Youting; Ye, Chaohui; Wang, Xiaojie; Ilghari, Dariush; Li, Xiaokun

2012-01-01

66

AMPK regulation of the growth of cultured human keratinocytes  

SciTech Connect

AMP kinase (AMPK) is a fuel sensing enzyme that responds to cellular energy depletion by increasing processes that generate ATP and inhibiting others that require ATP but are not acutely necessary for survival. In the present study, we examined the relationship between AMPK activation and the growth (proliferation) of cultured human keratinocytes and assessed whether the inhibition of keratinocyte growth by vitamin D involves AMPK activation. In addition, we explored whether the inhibition of keratinocyte proliferation as they approach confluence could be AMPK-related. Keratinocytes were incubated for 12 h with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside (AICAR). At concentrations of 10{sup -4} and 10{sup -3} M, AICAR inhibited keratinocyte growth by 50% and 95%, respectively, based on measurements of thymidine incorporation into DNA. It also increased AMPK and acetyl CoA carboxylase phosphorylation (P-AMPK and P-ACC) and decreased the concentration of malonyl CoA confirming that AMPK activation had occurred. Incubation with the thiazolidinedione, troglitazone (10{sup -6} M) caused similar alterations in P-AMPK, P-ACC, and cell growth. In contrast, the well known inhibition of keratinocyte growth by 1,25-dihydroxyvitamin D{sub 3} (10{sup -7} and 10{sup -6} M) was not associated with changes in P-AMPK or P-ACC. Like most cells, the growth of keratinocytes diminished as they approached confluence. Thus, it was of note that we found a progressive increase in P-AMPK (1.5- to 2-fold, p < 0.05) as keratinocytes grown in control medium went from 25% to 100% confluence. In conclusion, the data are consistent with the hypothesis that activation of AMPK acts as a signal to diminish the proliferation of cultured keratinocytes as they approach confluence. They also suggest that AMPK activators, such as AICAR and troglitazone, inhibit keratinocyte growth and that the inhibition of cell growth by 1,25-dihydroxyvitamin D{sub 3} is AMPK-independent.

Saha, Asish K. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States)]. E-mail: aksaha@bu.edu; Persons, Kelly [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Safer, Joshua D. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Luo Zhijun [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Holick, Michael F. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Ruderman, Neil B. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States)

2006-10-20

67

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling  

Microsoft Academic Search

The effects of exogenous hydrogen sulfide (H2S) on normal skin-derived immortalized human keratinocytes have been investigated in detail. We show in vitro that exogenous hydrogen sulfide reduces clonal growth, cell proliferation and cell adhesion of human keratinocytes. H2S, in fact, decreases the frequency of the putative keratinocyte stem cell subpopulation in culture, consequently affecting clonal growth, and impairs cell proliferation

Giuliana Gobbi; Francesca Ricci; Chiara Malinverno; Cecilia Carubbi; Maurizia Pambianco; Giuseppe de Panfilis; Marco Vitale; Prisco Mirandola

2009-01-01

68

UVA-Induced Cell Cycle Progression Is Mediated by a Disintegrin and Metalloprotease\\/Epidermal Growth Factor Receptor\\/AKT\\/Cyclin D1 Pathways in Keratinocytes  

Microsoft Academic Search

UVA (315-400 nm), which constitutes f95% of the UV irradiation in natural sunlight, represents a major environ- mental challenge to the skin and is clearly associated with human skin cancer. Here, we show that a low, nonlethal dose of UVA induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, whereas siRNA knockdown

Yu-Ying He; Sarah E. Council; Colin F. Chignell

2008-01-01

69

Induction of ?Np63 by the Newly Identified Keratinocyte-Specific Transforming Growth Factor ? Signaling Pathway with Smad2 and I?B Kinase ? in Squamous Cell Carcinoma12  

PubMed Central

The expression of p63 (TP63/p51) occurs in the basal cells of stratified epithelia and is strongly enhanced at the early stages of squamous cell carcinomas (SCCs) of the head and neck, skin, cervix, and others. We analyzed a promoter/enhancer region (2k?N) that drives the predominant expression of ?Np63 for sensitivity to Smad signaling pathways. Reporter assays in HepG2 cells showed a moderate activation of 2k?N by Smad2 and I?B kinase ? (IKK?), partners of the newly identified keratinocyte-specific transforming growth factor ? (TGF-?) signaling, but not by other Smad molecules. In A431 cells, 2k?N was activated by Smad2 and IKK?, for which a Smad binding element (SMD2) at -204 was essential. Binding of Smad2 to the chromosomal SMD2 site was detectable. The association of Smad2 with IKK? was evident in the nucleus of A431, accounting for the enhancement of ?Np63 expression by TGF-?. Moreover, both ?Np63 and IKK? were necessary to maintain the noninvasive phenotype of this cell line. FaDu, an invasive, Smad4-deficient SCC, also allowed 2k?N transactivation by transfected Smad2 in the presence of endogenous IKK?. Reflecting the lack of chromosomal SMD2-Smad2 association and the absence of nuclear IKK?, however, endogenous ?Np63 was not controlled by TGF-? or IKK? in FaDu. SCC tissue arrays showed nuclear accumulation of IKK? and p63 intensification in well-differentiated noninvasive lesions. This study indicates that p63 is a target gene of the proposed keratinocyte-specific TGF-? signal pathway for suppression of the malignant conversion of SCC. PMID:21170261

Fukunishi, Nahoko; Katoh, Iyoko; Tomimori, Yoshiya; Tsukinoki, Keiichi; Hata, Ryu-Ichiro; Nakao, Atsuhito; Ikawa, Yoji; Kurata, Shun-ichi

2010-01-01

70

Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth.  

PubMed

Interleukin-6 (IL-6) is one of the major inflammatory interleukins that has been linked to cancer progression. In our model for human skin squamous cell carcinoma (SCC), IL-6 expression is strongly upregulated upon progression from benign tumors to highly malignant, metastasizing SCCs. We now demonstrate that IL-6 promotes malignant and invasive tumor growth in human skin SCCs by inducing cell type specific cytokine profiles in tumor keratinocytes and stromal fibroblasts, activating the latter towards a tumor associated fibroblast (TAF) phenotype. In three-dimensional organotypic cocultures in vitro invasive growth of IL-6 overexpressing tumor keratinocytes, is associated with increased expression of matrix metalloproteinase-2 (MMP-2), MMP-14 and tissue inhibitor of metalloproteinases-2, and clearly depends on IL-6 activated fibroblasts. IL-6-induced secretion of monocyte chemotactic protein-1 (MCP-1) in tumor keratinocytes and of hepatocyte growth factor in fibroblasts is crucial for regulating expression and activation of MMP-2. This functional role of IL-6 is confirmed in vivo. Here MMP-14 and MMP-2 expression occur exclusively in surface transplants of IL-6 overexpressing keratinocytes and fibroblasts are identified as important source of MMP-2. Our data indicate that tumor keratinocytes derived IL-6 activates stromal fibroblasts towards a TAF phenotype, promoting tumor invasion via enhanced expression and activation of MMP-2. PMID:23165423

Depner, Sofia; Lederle, Wiltrud; Gutschalk, Claudia; Linde, Nina; Zajonz, Alexandra; Mueller, Margareta M

2014-08-01

71

BAG-1 enhances cell-cell adhesion, reduces proliferation and induces chaperone-independent suppression of hepatocyte growth factor-induced epidermal keratinocyte migration  

SciTech Connect

Cell motility is important in maintaining tissue homeostasis, facilitating epithelial wound repair and in tumour formation and progression. The aim of this study was to determine whether BAG-1 isoforms regulate epidermal cell migration in in vitro models of wound healing. In the human epidermal cell line HaCaT, endogenous BAG-1 is primarily nuclear and increases with confluence. Both transient and stable p36-Bag-1 overexpression resulted in increased cellular cohesion. Stable transfection of either of the three human BAG-1 isoforms p36-Bag-1 (BAG-1S), p46-Bag-1 (BAG-1M) and p50-Bag-1 (BAG-1L) inhibited growth and wound closure in serum-containing medium. However, in response to hepatocyte growth factor (HGF) in serum-free medium, BAG-1S/M reduced communal motility and colony scattering, but BAG-1L did not. In the presence of HGF, p36-Bag-1 transfectants retained proliferative response to HGF with no change in ERK1/2 activation. However, the cells retained E-cadherin localisation at cell-cell junctions and exhibited pronounced cortical actin. Point mutations in the BAG domain showed that BAG-1 inhibition of motility is independent of its function as a chaperone regulator. These findings are the first to suggest that BAG-1 plays a role in regulating cell-cell adhesion and suggest an important function in epidermal cohesion.

Hinitt, C.A.M.; Wood, J.; Lee, S.S. [Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY (United Kingdom)] [Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY (United Kingdom); Williams, A.C. [Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, University Walk, Bristol, BS8 1TD (United Kingdom)] [Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, University Walk, Bristol, BS8 1TD (United Kingdom); Howarth, J.L.; Glover, C.P.; Uney, J.B. [The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY (United Kingdom)] [The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY (United Kingdom); Hague, A., E-mail: a.hague@bristol.ac.uk [Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY (United Kingdom)

2010-08-01

72

Expression of paired-like homeodomain transcription factor 2c (PITX2c) in epidermal keratinocytes  

SciTech Connect

Paired-like homeodomain transcription factor 2 (PITX2) has been implicated as one of the genes responsible for Rieger syndrome. It has been also shown to play a central role during development. In this study, we investigated the functional role of PITX2 in keratinocyte differentiation. RT-PCR analysis showed that PITX2c isoform was predominantly expressed in a differentiation-dependent manner. Consistent with, immunohistochemical staining showed that PITX2 expression was increased in the upper layer of epidermis. When PITX2c was overexpressed in cultured keratinocytes by a recombinant adenovirus, the differentiation markers such as involucrin and loricrin were significantly increased at both mRNA and protein levels. In addition, PITX2c overexpression led to the decrease of cell growth, concomitantly with the upregulation of cell cycle-related genes p21. To investigate the effect of PITX2c in vivo, we microinjected PITX2c expression vector into zebrafish embryo. Interestingly, overexpression of PITX2c in zebrafish embryo led to the formation of horn-like structure and thickening of epidermis, together with the increase of keratin 8 (K8) expression. These results suggest that PITX2c has a role in proliferation and differentiation of epidermal keratinocytes.

Shi, Ge [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of) [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China); Sohn, Kyung-Cheol; Choi, Tae-Young; Choi, Dae-Kyoung; Lee, Sang-Sin [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of) [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Ou, Bai-sheng [Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China)] [Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China); Kim, Sooil; Lee, Young Ho [Department of Anatomy, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of)] [Department of Anatomy, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Yoon, Tae-Jin [Department of Dermatology, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of) [Department of Dermatology, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of); Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of); Kim, Seong-Jin [Department of Dermatology, Chonnam National University Medical School, Gwangju, 501-757 (Korea, Republic of)] [Department of Dermatology, Chonnam National University Medical School, Gwangju, 501-757 (Korea, Republic of); Lee, Young; Seo, Young-Joon; Lee, Jeung-Hoon [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of) [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Kim, Chang Deok, E-mail: cdkimd@cnu.ac.kr [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of)

2010-11-15

73

Interferon regulatory factor 6 is necessary, but not sufficient, for keratinocyte differentiation.  

PubMed

Regulation of epidermal proliferation and differentiation is critical for maintenance of cutaneous homeostasis. Interferon Regulatory Factor 6 (Irf6)-deficient mice die perinatally and exhibit ectopic proliferation and defective epidermal differentiation. We sought to determine whether these disruptions of epidermal function were cell autonomous, and used embryonic Irf6(-/-) keratinocytes to understand the specific role of Irf6 in keratinocyte proliferation and differentiation. In the absence of Irf6, keratinocytes exhibited a heterogeneous phenotype with the presence of large cells. Irf6(-/-) keratinocytes displayed increased colony-forming efficiency compared with wild-type cells, suggesting that Irf6 represses long-term proliferation. Irf6 was present at low levels in wild-type keratinocytes in culture, and upregulated after induction of differentiation in vitro, along with upregulation of markers of early differentiation. However, Irf6(-/-) keratinocytes did not express markers of terminal differentiation. Overexpression of Irf6 in wild-type keratinocytes was insufficient to induce expression of markers of differentiation under growing conditions. Together, these results indicated that Irf6 is necessary, but not sufficient, for keratinocyte differentiation. Finally, using a transgenic mouse expressing Lac-Z under the regulation of an enhancer element 9.7? kb upstream of the Irf6 start site, we demonstrated that this element contributes to the regulation of Irf6 in the epidermis and keratinocytes in culture. PMID:21918538

Biggs, Leah C; Rhea, Lindsey; Schutte, Brian C; Dunnwald, Martine

2012-01-01

74

Efficient keratinocyte differentiation strictly depends on JNK-induced soluble factors in fibroblasts.  

PubMed

Previous studies demonstrated that fibroblast-derived and JUN-dependent soluble factors have a crucial role on keratinocyte proliferation and differentiation during cutaneous wound healing. Furthermore, mice with a deficiency in Jun N-terminal kinases (JNKs) , JNK1 or JNK2, showed impaired skin development and delayed wound closure. To decipher the role of dermal JNK in keratinocyte behavior during these processes, we used a heterologous coculture model combining primary human keratinocytes and murine fibroblasts. Although cocultured JNK1/JNK2-deficient fibroblasts did not affect keratinocyte proliferation, temporal monitoring of the transcriptome of differentiating keratinocytes revealed that efficient keratinocyte differentiation not only requires the support by fibroblast-derived soluble factors, but is also critically dependent on JNK1 and JNK2 signaling in these cells. Moreover, we showed that the repertoire of fibroblast transcripts encoding secreted proteins is severely disarranged upon loss of JNK under the coculture conditions applied. Finally, our data demonstrate that efficient keratinocyte terminal differentiation requires constant presence of JNK-dependent and fibroblast-derived soluble factors. Taken together, our results imply that mesenchymal JNK has a pivotal role in the paracrine cross talk between dermal fibroblasts and epidermal keratinocytes during wound healing. PMID:24335928

Schumacher, Marion; Schuster, Christian; Rogon, Zbigniew M; Bauer, Tobias; Caushaj, Nevisa; Baars, Sebastian; Szabowski, Sibylle; Bauer, Christine; Schorpp-Kistner, Marina; Hess, Jochen; Holland-Cunz, Stefan; Wagner, Erwin F; Eils, Roland; Angel, Peter; Hartenstein, Bettina

2014-05-01

75

Investigation of the influence of keloid-derived keratinocytes on fibroblast growth and proliferation in vitro.  

PubMed

Keloids are disfiguring, proliferative scars that represent a pathological response to cutaneous injury. The overabundant extracellular matrix formation, largely from collagen deposition, is characteristic of these lesions and has led to investigations into the role of the fibroblast in its pathogenesis. Curiously, the role of the epidermis in extracellular matrix collagen deposition of normal skin has been established, but a similar hypothesis in keloids has not been investigated. The aim of this study was to investigate the influence of keloid epithelial keratinocytes on the growth and proliferation of normal fibroblasts in an in vitro serum-free co-culture system. A permeable membrane separated two chambers; the upper chamber contained a fully differentiated stratified epithelium derived from the skin of excised earlobe keloid specimens, whereas the lower chamber contained a monolayer of normal or keloid fibroblasts. Both cell types were nourished by serum-free medium from the lower chamber. Epithelial keratinocytes from five separate earlobe keloid specimens were investigated. Four sets of quadruplicates were performed for each specimen co-cultured with normal fibroblasts or keloid-derived fibroblasts. Controls consisted of (1) normal keratinocytes co-cultured with normal fibroblasts, and (2) fibroblasts grown in serum-free media in the absence of keratinocytes in the upper chamber. Fibroblasts were indirectly quantified by 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay, with results confirmed by DNA content measurement, at days 1 and 5 after the co- culture initiation.Significantly, increased proliferation was seen in fibroblasts co-cultured with keloid keratinocytes, as compared with the normal keratinocyte controls at day 5 (analysis of variance, p < 0.001). These results strongly suggest that the overlying epidermal keratinocytes of the keloid may have an important, previously unappreciated role in keloid pathogenesis using paracrine or epithelial-mesenchymal signaling. PMID:11304607

Lim, I J; Phan, T T; Song, C; Tan, W T; Longaker, M T

2001-03-01

76

Hair-Growth-Promoting Effect of Conditioned Medium of High Integrin ?6 and Low CD 71 (?6bri/CD71dim) Positive Keratinocyte Cells.  

PubMed

Keratinocyte stem/progenitor cells (KSCs) reside in the bulge region of the hair follicles and may be involved in hair growth. Hair follicle dermal papilla cells (HFDPCs) and outer root sheath (ORS) cells were treated with conditioned medium (CM) of KSCs. Moreover, the effects of KSC-CM on hair growth were examined ex vivo and in vivo. A human growth factor chip array and RT-PCR were employed to identify enriched proteins in KSC-CM as compared with CM from keratinocytes. KSC-CM significantly increased the proliferation of HFDPCs and ORS cells, and increased the S-phase of the cell cycle in HFDPCs. KSC-CM led to the phosphorylation of ATK and ERK1/2 in both cell types. After subcutaneous injection of KSC-CM in C3H/HeN mice, a significant increase in hair growth and increased proliferation of hair matrix keratinocytes ex vivo was observed. We identified six proteins enriched in KSC-CM (amphiregulin, insulin-like growth factor binding protein-2, insulin-like growth factor binding protein-5, granulocyte macrophage-colony stimulating factor, Platelet-derived growth factor-AA, and vascular endothelial growth factor). A growth-factor cocktail that contains these six recombinant growth factors significantly increased the proliferation of HFDPCs and ORS cells and enhanced the hair growth of mouse models. These results collectively indicate that KSC-CM has the potential to increase hair growth via the proliferative capacity of HFDPCs and ORS cells. PMID:25706512

Won, Chong Hyun; Jeong, Yun-Mi; Kang, Sangjin; Koo, Tae-Sung; Park, So-Hyun; Park, Ki-Young; Sung, Young-Kwan; Sung, Jong-Hyuk

2015-01-01

77

Ultraviolet B Radiation Upregulates the Production of Macrophage Migration Inhibitory Factor (MIF) in Human Epidermal Keratinocytes  

Microsoft Academic Search

Human epidermal cells are capable of secreting various cytokines with immunologic, inflammatory, and proliferative properties. In a previous study, by reverse transcription–polymerase chain reaction and immunohistochemical analysis, we have shown that human epidermal keratinocytes express macrophage migration inhibitory factor and identified its presence in the cytoplasm. In this study, we detected an increased serum macrophage migration inhibitory factor level by

Tadamichi Shimizu; Riichiro Abe; Akira Ohkawara; Jun Nishihira; J. Nishihira

1999-01-01

78

Role of myocyte enhancing factor 2B in epithelial myofibroblast transition of human gingival keratinocytes.  

PubMed

It has recently emerged that the myogenic contribution of the epithelial mesenchymal transition plays a role in neoplastic invasion and metastasis. Myocyte enhancing factor 2B (MEF2B) is the only MEF2 isoform expressed during early embryonic development, and is herein proposed to transactivate the downstream target proteins of the epithelial myofibroblast transition (EMyT). We have previously generated eight preneoplastic cell lines with spindle and cobblestone morphology from human gingival mucosal keratinocytes immortalized by E6/E7 of human papillomavirus type 16. Spindle cells formed tubulogenic morphogenesis on Matrigel and exhibited contractility, anchorage-independent growth and invasiveness to a greater extent than cobblestone cells. Expression of MEF2B mRNA and myofibroblast proteins was higher in spindle cells compared with cobblestone cells. Epidermal growth factor (EGF) treatment of cobblestone cells also induced expression of these genes. Knockdown of MEF2B in a cobblestone cell line abolished EGF-induced upregulation of MEF2, vimentin and non-muscle caldesmon proteins, but enhanced basal expression of mesenchymal vimentin and fibronectin. Differential regulation of intermediate filaments revealed an unrecognized role of MEF2B in myogenic transformation of the epithelial to a myofibroblast phenotype, which occurs as epithelioid variants in some soft tissue sarcomas. PMID:22302709

Sun, Qiang; Sattayakhom, Apsorn; Backs, Johannes; Stremmel, Wolfgang; Chamulitrat, Walee

2012-02-01

79

DeDifferentiation of Mouse Interfollicular Keratinocytes by the Embryonic Transcription Factor Oct-4  

Microsoft Academic Search

The embryonic transcription factor Oct-4 is often referred to as the master regulator of the undifferentiated state. Although its role in maintaining embryonic stem (ES) cell pluripotency is well established, its ability to directly reprogram committed somatic cells is not well defined. Using transient transfection, we tested its ability to revert mouse interfollicular epidermal basal keratinocytes to a more ES

Katie L Grinnell; Baoli Yang; Richard L Eckert; Jackie R Bickenbach

2007-01-01

80

8-Cl-Adenosine Induces Growth Arrest without Differentiation of Primary Mouse Epidermal Keratinocytes  

Microsoft Academic Search

In some cell systems, the antiproliferative effects of 8-Cl-cAMP, a site-selective cAMP analog specific for the type I cAMP-dependent protein kinase, are mediated by its metabolite, 8-Cl-adenosine. These effects were once thought to be specific to transformed cells. We investigated the ability of 8-Cl-adenosine to regulate growth and differentiation in primary cultures of mouse epidermal keratinocytes. A 24 h exposure

Daniel T. Dransfield; Richard D. Griner; Sagarika Ray; Meral Keskintepe; Wendy B. Bollag

2001-01-01

81

Hypoxia-inducible factor-1a regulates the expression of nucleotide excision repair proteins in keratinocytes  

Microsoft Academic Search

The regulation of DNA repair enzymes is crucial for cancer prevention, initiation, and therapy. We have studied the effect of ultraviolet B (UVB) radiation on the expression of the two nucleotide excision repair factors (XPC and XPD) in human keratinocytes. We show that hypoxia-inducible factor-1a (HIF-1a) is involved in the regulation of XPC and XPD. Early UVB-induced downregulation of HIF-1a

Hamid Reza Rezvani; Walid Mahfouf; Nsrein Ali; Cecile Chemin; Cecile Ged; Arianna L. Kim; Hubert de Verneuil; Alain Taieb; David R. Bickers; Frederic Mazurier

82

Expression of the human papillomavirus type 16 E7 oncoprotein induces an autophagy-related process and sensitizes normal human keratinocytes to cell death in response to growth factor deprivation  

SciTech Connect

Expression of oncogenes, such as the human papillomavirus type 16 (HPV16) E7 oncoprotein, promotes aberrant cell proliferation. In the absence of concurrent mitogenic stimuli, this triggers a cell-intrinsic defense mechanism, the 'trophic sentinel response', which eliminates such aberrant cells. The molecular pathways that elicit this response, however, remain obscure. We set up an experimental system to investigate the trophic sentinel pathway triggered by HPV16 E7 expression in normal human keratinocytes, the natural host cells of HPVs. Keratinocytes expressing HPV16 E7 cultured in E-medium undergo cell death and show increased sub-G1 DNA content when grown to confluence or under conditions of serum deprivation. Moreover, HPV16 E7 expressing human keratinocytes express higher levels of the autophagy marker, LC3-II, which can be abrogated by 3-methyladenine, an autophagy inhibitor. These findings indicate that even under normal culture conditions, HPV16 E7 expression triggers metabolic stress that may result in autophagy, a pathway implicated in carcinogenesis.

Zhou Xiaobo [Infectious Diseases Division, Channing Laboratories, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School (United States); Muenger, Karl [Infectious Diseases Division, Channing Laboratories, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School (United States)], E-mail: kmunger@rics.bwh.harvard.edu

2009-03-01

83

Dermal papilla cells express hepatocyte growth factor.  

PubMed

In the induction, development and maintenance of hair follicles, it is thought that an epithelial-mesenchymal interaction is important and that the dermal papilla plays some important roles. Hepatocyte growth factor is a multifunctional polypeptide which acts as mitogen, motogen or morphogen depending on the biological context. Recently, we found that HGF stimulates hair follicle growth in a mouse organ culture system, and therefore proceeded to investigate the expression of HGF on cultured human dermal papilla cells (DPC) and the effect of HGF on cultured human keratinocytes derived from hair bulb. Using an enzyme immuno assay, HGF immunoreactivities were not detected in conditioned media of DPC that were either non-treated or treated with TGF-beta, but were detected in conditioned media of DPC treated with IL1-alpha, TNF-alpha and TPA. Using the reverse transcription-polymerase chain reaction (RT-PCR) method, HGF mRNA was also detected in DPC. This expression was enhanced by IL1-alpha, TNF-alpha and TPA, but suppressed by TGF-beta. Furthermore, HGF stimulated the DNA synthesis in keratinocytes derived from human hair bulb in a dose-dependent manner. These results indicate that DPC express HGF in vitro and that HGF stimulates the growth of human keratinocytes derived from hair bulb in vitro. PMID:7999678

Shimaoka, S; Imai, R; Ogawa, H

1994-07-01

84

8-Cl-Adenosine enhances 1,25-dihydroxyvitamin D3-induced growth inhibition without affecting 1,25-dihydroxyvitamin D3-stimulated differentiation of primary mouse epidermal keratinocytes  

PubMed Central

Background Epidermal keratinocytes continuously proliferate and differentiate to form the mechanical and water permeability barrier that makes terrestrial life possible. In certain skin diseases, these processes become dysregulated, resulting in abnormal barrier formation. In particular, skin diseases such as psoriasis, actinic keratosis and basal and squamous cell carcinomas are characterized by hyperproliferation and aberrant or absent differentiation of epidermal keratinocytes. We previously demonstrated that 8-Cl-adenosine (8-Cl-Ado) can induce keratinocyte growth arrest without inducing differentiation. Results To determine if this agent might be useful in treating hyperproliferative skin disorders, we investigated whether 8-Cl-Ado could enhance the ability of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a known keratinocyte differentiating agent and a clinical treatment for psoriasis, to inhibit keratinocyte growth. We found that low concentrations of 8-Cl-Ado and 1,25(OH)2D3 appeared to act additively to reduce proliferation of primary mouse epidermal keratinocytes. However, another agent (transforming growth factor-beta) that triggers growth arrest without inducing differentiation also coincidentally inhibits differentiation elicited by other agents; inhibition of differentiation is suboptimal for treating skin disorders, as differentiation is often already reduced. Thus, we determined whether 8-Cl-Ado also decreased keratinocyte differentiation induced by 1,25(OH)2D3, as measured using the early and late differentiation markers, keratin 1 protein levels and transglutaminase activity, respectively. 8-Cl-Ado did not affect 1,25(OH)2D3-stimulated keratin 1 protein expression or transglutaminase activity. Conclusions Our results suggest that 8-Cl-Ado might be useful in combination with differentiating agents for the treatment of hyperproliferative disorders of the skin. PMID:15279680

Bollag, Wendy B; Zhong, Xiaofeng; Josephson, Sarah

2004-01-01

85

Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing.  

PubMed

The Nrf2 transcription factor is a key player in the cellular stress response through its regulation of cytoprotective genes. In this study we determined the role of Nrf2-mediated gene expression in keratinocytes for skin development, wound repair, and skin carcinogenesis. To overcome compensation by the related Nrf1 and Nrf3 proteins, we expressed a dominant-negative Nrf2 mutant (dnNrf2) in the epidermis of transgenic mice. The functionality of the transgene product was verified in vivo using mice doubly transgenic for dnNrf2 and an Nrf2-responsive reporter gene. Surprisingly, no abnormalities of the epidermis were observed in dnNrf2-transgenic mice, and even full-thickness skin wounds healed normally. However, the onset, incidence, and multiplicity of chemically induced skin papillomas were strikingly enhanced, whereas the progression to squamous cell carcinomas was unaltered. We provide evidence that the enhanced tumorigenesis results from reduced basal expression of cytoprotective Nrf target genes, leading to accumulation of oxidative damage and reduced carcinogen detoxification. Our results reveal a crucial role of Nrf-mediated gene expression in keratinocytes in the prevention of skin tumors and suggest that activation of Nrf2 in keratinocytes is a promising strategy to prevent carcinogenesis of this highly exposed organ. PMID:16648473

auf dem Keller, Ulrich; Huber, Marcel; Beyer, Tobias A; Kümin, Angelika; Siemes, Christina; Braun, Susanne; Bugnon, Philippe; Mitropoulos, Varvara; Johnson, Delinda A; Johnson, Jeffrey A; Hohl, Daniel; Werner, Sabine

2006-05-01

86

Connexin43 Reduces Melanoma Growth within a Keratinocyte Microenvironment and during Tumorigenesis in Vivo*  

PubMed Central

Connexins (Cx) have been identified as tumor suppressors or enhancers, a distinction that appears to be dependent on the type and stage of disease. However, the role of connexins in melanoma tumorigenesis and their status during cancer onset and progression remain controversial and unclear. Here, we show that the aggressive B16-BL6 mouse melanoma cell line expresses low basal levels of Cx26 and Cx43, rendering them gap junctional intercellular communication-deficient as elucidated by immunofluorescence, Western blotting, and dye transfer studies. Following ectopic expression of green fluorescent protein-tagged Cx26 and Cx43 in these connexin-deficient melanomas, punctate gap junction-like plaques were evident at sites of cell-cell apposition, and the incidence of dye transfer was significantly increased similar to connexin-rich keratinocytes. We found that the expression of Cx43, but not Cx26, significantly reduced cellular proliferation and anchorage-independent growth from control melanomas, whereas migration was unaffected. Additionally, melanomas expressing Cx43 displayed significantly reduced growth within the in situ-like microenvironment of keratinocytes, despite a lack of heterocellular gap junctional intercellular communication between the two cell types. Furthermore, when grown in vivo in the chicken chorioallantoic membrane, primary tumors derived from Cx43-expressing melanomas were significantly smaller than controls, whereas Cx26-expressing melanomas produced tumors similar to controls. Collectively, these results suggest that Cx43, and not Cx26, can act as a tumor suppressor during melanoma tumorigenesis. PMID:24297173

Ableser, Mark J.; Penuela, Silvia; Lee, Jack; Shao, Qing; Laird, Dale W.

2014-01-01

87

Knockdown of PKD1 in normal human epidermal keratinocytes increases mRNA expression of keratin 10 and involucrin: early markers of keratinocyte differentiation  

Microsoft Academic Search

Subconfluent normal human keratinocytes exhibit autonomous (autocrine growth factor driven) proliferation and express the\\u000a specific markers for keratinocyte proliferation K5 (keratin 5) and K14 (keratin 14). Utilizing this model the effects of PKD1\\u000a (Protein kinase D1) knockdown on activation of differentiation was studied. siRNA approach was applied to achieve specific\\u000a knockdown of PKD1 and the mRNA levels of different keratinocyte

Petya Ivanova; Ganka Atanasova; Yves Poumay; Vanyo Mitev

2008-01-01

88

Tumor necrosis factor-?-induced CTACK\\/CCL27 (cutaneous T-cell-attracting chemokine) production in keratinocytes is controlled by nuclear factor ?B  

Microsoft Academic Search

CTACK\\/CCL27 is pivotal in mediating the migration of lymphocytes into the skin, through the binding to the chemokine receptor CCR10. CCL27 is continuously expressed by keratinocytes, but highly upregulated in inflammatory skin diseases such as atopic dermatitis and psoriasis. CCL27 can be induced in cultured keratinocytes by tumor necrosis factor (TNF)-?, which is also known to induce activity of the

Christian Vestergaard; Claus Johansen; Kristian Otkjaer; Mette Deleuran; Lars Iversen

2005-01-01

89

Safe Selection of Genetically Manipulated Human Primary Keratinocytes with Very High Growth Potential Using CD24  

Microsoft Academic Search

Stable and safe corrective gene transfer in stem keratinocytes is necessary for ensuring success in cutaneous gene therapy. There have been numerous encouraging preclinical approaches to cutaneous gene therapy in the past decade, but it is only recently that a human volunteer suffering from junctional epidermolysis bullosa could be successfully grafted using his own non-selected, genetically corrected epidermal keratinocytes. However,

Valérie Bergoglio; Fernando Larcher; Odile Chevallier-Lagente; Alain Bernheim; Olivier Danos; Alain Sarasin; Marcela Del Rio; Thierry Magnaldo

2007-01-01

90

Reactive Oxygen Species in Tumor Necrosis Factor-?-Activated Primary Human Keratinocytes: Implications for Psoriasis and Inflammatory Skin Disease  

Microsoft Academic Search

The multifunctional cytokine tumor necrosis factor-? (TNF-?) is known to play an important role in inflammatory and immunological responses in human skin. Although it has been documented that reactive oxygen species (ROS) are involved in TNF-?-induced signaling pathways associated with certain inflammatory diseases, their role in TNF-? signaling cascades has not been examined in primary human keratinocytes used as a

Chen N Young; Jay I Koepke; Laura J Terlecky; Michael S Borkin; Savoy L Boyd; Stanley R Terlecky

2008-01-01

91

Modulation of TGF?-inducible hypermotility by EGF and other factors in human prostate epithelial cells and keratinocytes  

PubMed Central

Keratinocytes migrating from a wound edge or initiating malignant invasion greatly increase their expression of the basement membrane protein Laminin-322 (Lam332). In culture, keratinocytes initiate sustained directional hypermotility when plated onto an incompletely processed form of Lam332 (Lam332?) or when treated with TGF?, an inducer of Lam332 expression. The development and tissue architecture of stratified squamous and prostate epithelia are very different, yet the basal cells of both express p63, ?6?4 integrin, and Lam332. Keratinocytes and prostate epithelial cells grow well in nutritionally-optimized culture media with pituitary extract and certain mitogens. We report that prostate epithelial cells display hypermotility responses indistinguishable from those of keratinocytes. Several culture medium variables attenuated TGF?-induced hypermotility, including Ca++, serum, and some pituitary extract preparations, without impairing growth, TGF? growth-inhibition, or hypermotility on Lam322?. Distinct from its role as a mitogen, EGF proved to be a required cofactor for TGF?-induced hypermotility and could not be replaced by HGF or KGF. Prostate epithelial cells have a short replicative lifespan, restricted both by p16INK4A and telomere-related mechanisms. We immortalized the normal prostate epithelial cell line HPrE-1 by transduction to express bmi1 and TERT. Prostate epithelial cells lose expression of p63, ?4 integrin, and Lam332 when they transform to invasive carcinoma. In contrast, HPrE-1/bmi1/TERT cells retained expression of these proteins and normal TGF? signaling and hypermotility for >100 doublings. Thus, keratinocytes and prostate epithelial cells possess common hypermotility and senescence mechanisms and immortalized prostate cell lines can be engineered using defined methods to yield cells retaining normal properties. PMID:21042878

Wei, Wei; Barron, Patricia D.; Rheinwald, James G.

2013-01-01

92

FGF growth factor analogs  

DOEpatents

The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

Zamora, Paul O. (Gaithersburg, MD); Pena, Louis A. (Poquott, NY); Lin, Xinhua (Plainview, NY); Takahashi, Kazuyuki (Germantown, MD)

2012-07-24

93

Growth factors for nanobacteria  

NASA Astrophysics Data System (ADS)

Nanobacteria are novel microorganisms recently isolated from fetal bovine serum and blood of cows and humans. These coccoid, gram negative bacteria in alpha-2 subgroup of Proteobacteria grow slowly under mammalian cell culture conditions but not in common media for microbes. Now we have found two different kinds of culture supplement preparations that improve their growth and make them culturable in the classical sense. These are supernatant fractions of conditioned media obtained from 1 - 3 months old nanobacteria cultures and from about a 2 weeks old Bacillus species culture. Both improved multiplication and particle yields and the latter increased their resistance to gentamicin. Nanobacteria cultured with any of the methods shared similar immunological property, structure and protein pattern. The growth supporting factors were heat-stabile and nondialyzable, and dialysis improved the growth promoting action. Nanobacteria formed stony colonies in a bacteriological medium supplemented with the growth factors. This is an implication that nanobacterial growth is influenced by pre-existing bacterial flora.

Ciftcioglu, Neva; Kajander, E. Olavi

1999-12-01

94

New microbial growth factor.  

PubMed Central

A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a new microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight, and it has high specific activity. When added to the diets for a meadow vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain. PMID:327929

Bok, S H; Casida, L E

1977-01-01

95

New microbial growth factor  

NASA Technical Reports Server (NTRS)

A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a previously unknown microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight and has high specific activity. When added to the diets for a meadow-vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain.

Bok, S. H.; Casida, L. E., Jr.

1977-01-01

96

Myeloid growth factors.  

PubMed

Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony-stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting. PMID:24142827

Crawford, Jeffrey; Armitage, James; Balducci, Lodovico; Becker, Pamela Sue; Blayney, Douglas W; Cataland, Spero R; Heaney, Mark L; Hudock, Susan; Kloth, Dwight D; Kuter, David J; Lyman, Gary H; McMahon, Brandon; Rugo, Hope S; Saad, Ayman A; Schwartzberg, Lee S; Shayani, Sepideh; Steensma, David P; Talbott, Mahsa; Vadhan-Raj, Saroj; Westervelt, Peter; Westmoreland, Michael; Dwyer, Mary; Ho, Maria

2013-10-01

97

Fibrotic remodeling of tissue-engineered skin with deep dermal fibroblasts is reduced by keratinocytes.  

PubMed

Two-thirds of burn patients with deep dermal injuries are affected by hypertrophic scars, and currently, there are no clinically effective therapies. Tissue-engineered skin is a very promising model for the elucidation of the role of matrix microenvironment and biomechanical characteristics and could help in the identification of new therapeutic targets for hypertrophic scars. Conventionally, tissue-engineered skin is made of heterogeneous dermal fibroblasts and keratinocytes; however, recent work has shown that superficial and deep dermal fibroblasts are antifibrotic and profibrotic, respectively. Furthermore, keratinocytes are believed to regulate the development and remodeling of fibrosis in skin. This study aimed to assess the influence of keratinocytes and layered fibroblasts on the characteristics of tissue-engineered skin. Layered fibroblasts and keratinocytes isolated from superficial and deep dermis and epidermis, respectively, of the lower abdominal tissue were independently co-cultured on collagen-glycosaminoglycan scaffolds, and the resulting tissue-engineered skin was assessed for differences in tissue remodeling based on the underlying specific dermal fibroblast subpopulation. Collagen production by deep fibroblasts but not by superficial fibroblasts was significantly reduced upon co-culture with keratinocytes. Also, keratinocytes in the tissue-engineered skin resulted in significantly reduced expression of profibrotic connective tissue growth factor and fibronectin, and increased expression of the antifibrotic matrix metalloproteinase-1 by deep fibroblasts but not by superficial fibroblasts. Tissue-engineered skin made of deep fibroblasts and keratinocytes had lower levels of small proteoglycans, decorin, and fibromodulin, and higher levels of large proteoglycan, versican, compared to tissue-engineered skin made of superficial fibroblasts and keratinocytes. Tissue-engineered skin made of deep fibroblasts and keratinocytes had lower expression of transforming growth factor (TGF)-?, interleukin (IL)-1, and keratinocyte growth factor but higher expression of platelet-derived growth factor and IL-6, compared to tissue-engineered skin made of superficial fibroblasts and keratinocytes. Furthermore, co-culture with keratinocytes reduced TGF-?1 production of deep but not superficial fibroblasts. Additionally, keratinocytes reduced the differentiation of deep fibroblasts to myofibroblasts in tissue-engineered skin constructs, but not that of superficial fibroblasts. Taken together, keratinocytes reduce fibrotic remodeling of the scaffolds by deep dermal fibroblasts. Our results therefore demonstrate that tissue-engineered skin made specifically with a homogeneous population of superficial fibroblasts and keratinocytes is less fibrotic than that with a heterogeneous population of fibroblasts and keratinocytes. PMID:24090416

Varkey, Mathew; Ding, Jie; Tredget, Edward E

2014-02-01

98

Epidermal growth factor receptor distribution in burn wounds. Implications for growth factor-mediated repair.  

PubMed Central

Epidermal growth factor (EGF) along with several related peptide growth factors has been shown both in vivo and in vitro to accelerate events associated with epidermal wound repair. EGF and transforming growth factor alpha act by binding to a common EGF receptor tyrosine kinase thereby initiating a series of events which ultimately regulate cell proliferation. This study examined the immunohistochemical localization of EGF receptor (EGF-R) in burn wound margins, adjacent proliferating epithelium, and closely associated sweat ducts, sebaceous glands, and hair follicles. Tissue specimens removed during surgical debridement were obtained from full and partial thickness burn wounds in 32 patients with total body surface area burns ranging from 2 to 88%. In the early postburn period (days 2-4), prominent staining for EGF-R was found in undifferentiated, marginal keratinocytes, adjacent proliferating, hypertrophic epithelium, and both marginal and nonmarginal hair follicles, sweat ducts, and sebaceous glands. During the late postburn period (days 5-16), EGF-R was depleted along leading epithelial margins; however, immunoreactive EGF-R remained intensely positive in the hypertrophic epithelium and all skin appendages. Increased detection of immunoreactive EGF-R and the presence of [125I]EGF binding in the hypertrophic epithelium correlated positively with proliferating cell nuclear antigen distributions. Thus, the presence of EGF-R in the appropriate keratinocyte populations suggests a functional role for this receptor during wound repair. Dynamic modulation in EGF receptor distribution during the temporal sequence of repair provides further evidence that an EGF/transforming growth factor alpha/EGF-R-mediated pathway is activated during human wound repair. Images PMID:1361495

Wenczak, B A; Lynch, J B; Nanney, L B

1992-01-01

99

Role of Growth Factors, Cytokines, and Their Receptors in the Pathogenesis of Psoriasis  

Microsoft Academic Search

Psoriasis is characterized by epidermal hyperplasia, altered epidermal maturation, and local accumulation of acute and chronic inflammatory cells. Keratinocyte hyperplasia in psoriasis may be explained in part by overproduction of growth factors or cytokines which stimulate epidermal proliferation and by altered metabolism of growth-factor receptors in affected skin. Psoriatic epidermis displays overproduction of TGF-alpha and interleukin-6 (IL-6), factors produced by

James G. Krueger; Jeffrey F. Krane; D. Martin Carter; Alice B. Gottlieb

1990-01-01

100

Tanshinone IIA Inhibits Growth of Keratinocytes through Cell Cycle Arrest and Apoptosis: Underlying Treatment Mechanism of Psoriasis  

PubMed Central

The aim of the present investigation was to elucidate the cellular mechanisms whereby Tanshinone IIA (Tan IIA) leads to cell cycle arrest and apoptosis in vitro in keratinocytes, the target cells in psoriasis. Tan IIA inhibited proliferation of mouse keratinocytes in a dose- and time-dependent manner and induced apoptosis, resulting in S phase arrest accompanied by down-regulation of pCdk2 and cyclin A protein expression. Furthermore, Tan IIA-induced apoptosis and mitochondrial membrane potential changes were also further demonstrated by DNA fragmentation, single-cell gel electrophoresis assay (SCGE), and flow cytometry methods. Apoptosis was partially blocked by the caspase-3 inhibitor Ac-DEVD-CHO. Mitochondrial regulation of apoptosis further downstream was investigated, showing changes in the mitochondrial membrane potential, cytochrome c release into the cytoplasm, and enhanced activation of cleaved caspase-3 and Poly ADP-ribose polymerase (PARP). There was also no translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus in apoptotic keratinocytes, indicating Tan IIA-induced apoptosis occurs mainly through the caspase pathway. Our findings provide the molecular mechanisms by which Tan IIA can be used to treat psoriasis and support the traditional use of Salvia miltiorrhiza Bungee (Labiatae) for psoriasis and related skin diseases. PMID:22203883

Li, Fu-Lun; Xu, Rong; Zeng, Qing-chun; Li, Xin; Chen, Jie; Wang, Yi-Fei; Fan, Bin; Geng, Lin; Li, Bin

2012-01-01

101

RXR? ablation in epidermal keratinocytes enhances UV radiation induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes  

PubMed Central

We show here that keratinocytic nuclear receptor Retinoid X Receptor ? (RXR?) regulates mouse keratinocyte and melanocyte homeostasis following acute ultraviolet radiation (UVR). Keratinocytic RXR? has a protective role on UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress mediated DNA damage and cellular apoptosis. We discovered that keratinocytic RXR? in a cell autonomous manner regulate mitogenic growth responses in skin epidermis via secretion of hbEGF, GMCSF, IL1-? and COX2, and activation of MAPK pathways. We identified altered expression of several keratinocyte-derived mitogenic paracrine growth factors such as ET-1, HGF, ?–MSH, SCF and FGF2 in skin of mice lacking RXR? in epidermal keratinocytes (RXR?ep?/? mice), which in a non-cell autonomous manner modulated melanocyte proliferation and activation after UVR. RXR?ep?/? mouse represents a unique animal model where UVR induces melanocyte proliferation/activation in both epidermis and dermis. Considered together, our results suggest that RXR antagonists, together with inhibitors of cell proliferation can be effective to prevent solar UV radiation induced photo-carcinogenesis. PMID:20944655

Wang, Zhixing; Coleman, Daniel J.; Bajaj, Gaurav; Liang, Xiaobo; Ganguli-Indra, Gitali; Indra, Arup Kumar

2011-01-01

102

Stathmin Regulates Keratinocyte Proliferation and Migration during Cutaneous Regeneration  

PubMed Central

Cutaneous regeneration utilizes paracrine feedback mechanisms to fine-tune the regulation of epidermal keratinocyte proliferation and migration. However, it is unknown how fibroblast-derived hepatocyte growth factor (HGF) affects these mutually exclusive processes in distinct cell populations. We here show that HGF stimulates the expression and phosphorylation of the microtubule-destabilizing factor stathmin in primary human keratinocytes. Quantitative single cell- and cell population-based analyses revealed that basal stathmin levels are important for the migratory ability of keratinocytes in vitro; however, its expression is moderately induced in the migration tongue of mouse skin or organotypic multi-layered keratinocyte 3D cultures after full-thickness wounding. In contrast, clearly elevated stathmin expression is detectable in hyperproliferative epidermal areas. In vitro, stathmin silencing significantly reduced keratinocyte proliferation. Automated quantitative and time-resolved analyses in organotypic cocultures demonstrated a high correlation between Stathmin/phospho-Stathmin and Ki67 positivity in epidermal regions with proliferative activity. Thus, activation of stathmin may stimulate keratinocyte proliferation, while basal stathmin levels are sufficient for keratinocyte migration during cutaneous regeneration. PMID:24066165

Schmitt, Sabrina; Safferling, Kai; Westphal, Kathi; Hrabowski, Manuel; Müller, Ute; Angel, Peter; Wiechert, Lars; Ehemann, Volker; Müller, Benedikt; Holland-Cunz, Stefan; Stichel, Damian; Harder, Nathalie; Rohr, Karl; Germann, Günter; Matthäus, Franziska; Schirmacher, Peter; Grabe, Niels; Breuhahn, Kai

2013-01-01

103

Receptor-interacting protein kinase 4 and interferon regulatory factor 6 function as a signaling axis to regulate keratinocyte differentiation.  

PubMed

Receptor-interacting protein kinase 4 (RIPK4) and interferon regulatory factor 6 (IRF6) are critical regulators of keratinocyte differentiation, and their mutation causes the related developmental epidermal disorders Bartsocas-Papas syndrome and popliteal pterygium syndrome, respectively. However, the signaling pathways in which RIPK4 and IRF6 operate to regulate keratinocyte differentiation are poorly defined. Here we identify and mechanistically define a direct functional relationship between RIPK4 and IRF6. Gene promoter reporter and in vitro kinase assays, coimmunoprecipitation experiments, and confocal microscopy demonstrated that RIPK4 directly regulates IRF6 trans-activator activity and nuclear translocation. Gene knockdown and overexpression studies indicated that the RIPK4-IRF6 signaling axis controls the expression of key transcriptional regulators of keratinocyte differentiation, including Grainyhead-like 3 and OVO-like 1. Additionally, we demonstrate that the p.Ile121Asn missense mutation in RIPK4, which has been identified recently in Bartsocas-Papas syndrome, inhibits its kinase activity, thereby preventing RIPK4-mediated IRF6 activation and nuclear translocation. We show, through mutagenesis-based experiments, that Ser-413 and Ser-424 in IRF6 are important for its activation by RIPK4. RIPK4 is also important for the regulation of IRF6 expression by the protein kinase C pathway. Therefore, our findings not only provide important mechanistic insights into the regulation of keratinocyte differentiation by RIPK4 and IRF6, but they also suggest one mechanism by which mutations in RIPK4 may cause epidermal disorders (e.g. Bartsocas-Papas syndrome), namely by the impaired activation of IRF6 by RIPK4. PMID:25246526

Kwa, Mei Qi; Huynh, Jennifer; Aw, Jiamin; Zhang, Lianyi; Nguyen, Thao; Reynolds, Eric C; Sweet, Matthew J; Hamilton, John A; Scholz, Glen M

2014-11-01

104

Acute and chronic wound fluids influence keratinocyte function differently.  

PubMed

Wound healing requires a proper functioning of keratinocytes that migrate, proliferate and lead to a competent wound closure. Impaired wound healing might be due to a disturbed keratinocyte function caused by the wound environment. Basically, chronic wound fluid (CWF) differs from acute wound fluid (AWF). The aim of this study was to analyse the effects of AWF and CWF on keratinocyte function. We therefore investigated keratinocyte migration and proliferation under the influence of AWF and CWF using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test and scratch assay. We further measured the gene expression by qRT-PCR regarding growth factors and matrixmetalloproteinases (MMPs) involved in regeneration processes. AWF had a positive impact on keratinocyte proliferation over time, whereas CWF had an anti-proliferative effect. Keratinocyte migration was significantly impaired by CWF in contrast to an undisturbed wound closure under the influence of AWF. MMP-9 expression was strongly upregulated by CWF compared with AWF. Keratinocyte function was significantly impaired by CWF. An excessive induction of MMP-9 by CWF might lead to a permanent degradation of extracellular matrix and thereby prevent wounds from healing. PMID:23517467

Thamm, Oliver C; Koenen, Paola; Bader, Nicola; Schneider, Alina; Wutzler, Sebastian; Neugebauer, Edmund Am; Spanholtz, Timo A

2015-04-01

105

Effect of Wnt3a on Keratinocytes Utilizing in Vitro and Bioinformatics Analysis  

PubMed Central

Wingless-type (Wnt) signaling proteins participate in various cell developmental processes. A suppressive role of Wnt5a on keratinocyte growth has already been observed. However, the role of other Wnt proteins in proliferation and differentiation of keratinocytes remains unknown. Here, we investigated the effects of the Wnt ligand, Wnt3a, on proliferation and differentiation of keratinocytes. Keratinocytes from normal human skin were cultured and treated with recombinant Wnt3a alone or in combination with the inflammatory cytokine, tumor necrosis factor ? (TNF?). Furthermore, using bioinformatics, we analyzed the biochemical parameters, molecular evolution, and protein–protein interaction network for the Wnt family. Application of recombinant Wnt3a showed an anti-proliferative effect on keratinocytes in a dose-dependent manner. After treatment with TNF?, Wnt3a still demonstrated an anti-proliferative effect on human keratinocytes. Exogenous treatment of Wnt3a was unable to alter mRNA expression of differentiation markers of keratinocytes, whereas an altered expression was observed in TNF?-stimulated keratinocytes. In silico phylogenetic, biochemical, and protein–protein interaction analysis showed several close relationships among the family members of the Wnt family. Moreover, a close phylogenetic and biochemical similarity was observed between Wnt3a and Wnt5a. Finally, we proposed a hypothetical mechanism to illustrate how the Wnt3a protein may inhibit the process of proliferation in keratinocytes, which would be useful for future researchers. PMID:24686518

Nam, Ju-Suk; Chakraborty, Chiranjib; Sharma, Ashish Ranjan; Her, Young; Bae, Kee-Jeong; Sharma, Garima; Doss, George Priya; Lee, Sang-Soo; Hong, Myung-Sun; Song, Dong-Keun

2014-01-01

106

Mutual induction of growth factor gene expression by epidermal-dermal cell interaction  

PubMed Central

Epithelial-mesenchymal interactions control epidermal growth and differentiation, but little is known about the mechanisms of this interaction. We have examined the effects of human dermal microvascular endothelial cells (DMEC) and fibroblasts on keratinocytes in conventional (feeder layer) and organotypic cocultures (lifted collagen gels) and demonstrated the induction of paracrine growth factor gene expression. Clonal keratinocyte growth was similarly stimulated in cocultures with irradiated DMEC and fibroblasts as feeder cells. This effect is most probably caused by induction of growth factor expression in cocultured dermal cells. Keratinocytes stimulated mRNA levels for KGF and IL-6 in both mesenchymal cell types and GM-CSF in fibroblasts. The feeder effect could not be replaced by conditioned media or addition of isolated growth factors. In organotypic cocultures with keratinocytes growing on collagen gels (repopulated with dermal cells), a virtually normal epidermis was formed within 7 to 10 d. Keratinocyte proliferation was drastically stimulated by dermal cells (histone 3 mRNA expression and BrdU labeling) which continued to proliferate as well in the gel. Expression of all typical differentiation markers was provoked in the reconstituted epithelium, though with different localization as compared to normal epidermis. Keratins K1 and K10 appeared coexpressed but delayed, reflecting conditions in epidermal hyperplasia. Keratin localization and proliferation were normalized under in vivo conditions, i.e., in surface transplants on nude mice. From these data it is concluded that epidermal homeostasis is in part controlled by complex reciprocally induced paracrine acting factors in concert with cell-cell interactions and extracellular matrix influences. PMID:8320264

1993-01-01

107

The oncogenic GLI transcription factors facilitate keratinocyte survival and transformation upon exposure to genotoxic agents.  

PubMed

Ultraviolet B (UVB) light is the principal aetiological factor associated with non-melanoma skin cancer, the most prevalent group of malignancies in the Caucasian population. Exposure to environmental chemicals has also been shown to promote skin carcinogenesis and, as for UVB, this is associated with the acquisition of genomic DNA damage. Cells respond to DNA damage by inducing cell cycle arrest to facilitate DNA repair, although apoptosis will occur if the damage is excessive. Oncogenes may drive carcinogenesis by disrupting the balanced control of cell cycle progression, DNA repair and apoptosis, allowing for the propagation of cells with damaged DNA. The transcription factors GLI1 and GLI2 have been implicated in both the initiation and progression of several cancers, including basal cell carcinoma. Here we show that GLI1 and an active mutant of GLI2 (?NGLI2) promote apoptotic resistance in N/TERT human keratinocytes upon exposure to UVB and the DNA-alkylating chemicals such as methyl methanesulphonate (MMS) and N-ethyl-N-nitrosurea. Compared with control and untreated N/TERT-GLI1 and -GLI2 cells, those that survived genotoxic insult formed significantly more colonies in soft agar and were significantly more invasive when grown in three-dimensional organotypic collagen gel cultures. Indeed, surviving N/TERT-GLI1 and -GLI2 cells expressed higher levels of the epithelial-to-mesenchymal transition markers Snail and vimentin, and a subpopulation of MMS-treated cells displayed an elongated fibroblast-like morphology with decreased levels of E-cadherin. Finally, whereas Bcl2 was strongly increased in N/TERT-GLI2 cells, the level of induction was weak in N/TERT-GLI1 cells, indicating that GLI1 may activate anti-apoptotic mechanisms(s) independently of Bcl2. In summary, our results show that GLI1 and GLI2 facilitate the propagation of cells with damaged DNA, and thus their expression may be naturally higher in cells that form the earliest precursor tumour lesions. PMID:23792444

Harrison, W; Cochrane, B; Neill, G; Philpott, M

2014-05-01

108

Growth and differentiation of normal human melanocytes in a TPA-free, cholera toxin-free, low-serum medium and influence of keratinocytes  

Microsoft Academic Search

Melanocyte cultures were obtained from a modification of the keratinocyte culture system MCDB153. Either promelanocytes or mature melanocytes were selected from epidermal cell primary cultures. Pure subcultures of actively dividing melanocytes of both types were grown in a low-serum medium totally deprived of TPA and cholera toxin called melanocyte growth medium (MGM). Early passaged cells from MGM primary cocultures were

P. Donatien; J. E. Surlève-Bazeille; A. J. Thody; A. TaÏeb

1993-01-01

109

Keratinocyte G2\\/M Growth Arrest by 1,25-Dihydroxyvitamin D3 Is Caused by Cdc2 Phosphorylation Through Wee1 and Myt1 Regulation  

Microsoft Academic Search

1,25-dihydroxyvitamin D3 (1,25[OH]2VD3) has an antiproliferative effect on keratinocyte growth, and its derivatives are used for the treatment of psoriasis. It was reported previously that 1,25[OH]2VD3 induced cell cycle arrest not only at the G0\\/G1 phase but also at the G2\\/M phase. However, the mechanism of 1,25[OH]2VD3-induced G2\\/M phase arrest in keratinocytes has not been fully understood. The addition of

Xiuju Dai; Kenshi Yamasaki; Lujun Yang; Koji Sayama; Yuji Shirakata; Sho Tokumara; Yoko Yahata; Mikiko Tohyama; Koji Hashimoto

2004-01-01

110

Protein Kinase C ? Increases Kruppel-like Factor 4 Protein, which Drives Involucrin Gene Transcription in Differentiating Keratinocytes*  

PubMed Central

KLF4 is a member of the Kruppel-like factor family of transcriptional regulators. KLF4 has been shown to be required for normal terminal differentiation of keratinocytes, but the molecular mechanism whereby KLF4 regulates genes associated with the differentiation process has not been studied. In the present study, we explore the impact of KLF4 on expression of involucrin, a gene that is specifically expressed in differentiated keratinocytes. KLF4 overexpression and knockdown studies show that involucrin mRNA and protein level correlates directly with KLF4 level. Moreover, studies of mutant KLF4 proteins indicate that transcriptionally inactive forms do not increase involucrin expression. PKC? is a regulator of keratinocyte differentiation that increases expression of differentiation-associated target genes, including involucrin. Overexpression of KLF4 augments the PKC?-dependent increase in involucrin expression, whereas KLF4 knockdown attenuates this response. The KLF4 induction of human involucrin (hINV) promoter activity is mediated via KLF4 binding to a GC-rich element located in the hINV promoter distal regulatory region, a region of the promoter required for in vivo involucrin expression. Mutation of the GC-rich element, an adjacent AP1 factor binding site, or both sites severely attenuates the response. Moreover, loss of KLF4 in an epidermal equivalent model of differentiation results in loss of hINV expression. These studies suggest that KLF4 is part of a multiprotein complex that interacts that the hINV promoter distal regulatory region to drive differentiation-dependent hINV gene expression in epidermis. PMID:23599428

Chew, Yap Ching; Adhikary, Gautam; Xu, Wen; Wilson, Gerald M.; Eckert, Richard L.

2013-01-01

111

[The keratinocyte].  

PubMed

This review summarizes recent data on the keratinocyte, the major cell type in the epidermis. A two-state model is proposed: in the "resting" state, the keratinocyte is committed to a program of terminal differentiation focusing on production of an efficient barrier, the stratum corneum, and of the epidermal basement membrane; the activated state, first discovered in cell culture studies, occurs in vivo during epidermal wound healing and inflammatory skin diseases. PMID:1376889

Taïeb, A

1992-02-01

112

Growth hormone, growth factors, and acromegaly  

SciTech Connect

This book contains five sections, each consisting of several papers. The section headings are: Biochemistry and Physiology of GH and Growth Factors, Pathology of Acromegaly, Clinical Endocrinology of Acromegaly, Nonsurgical Therapy of Acromegaly, and Surgical Therapy of Acromegaly.

Ludecke, D.K.; Tolis, G.T.

1987-01-01

113

Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF{kappa}B and AhR and EGFR-ERK pathway  

SciTech Connect

Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA + UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure, the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50 {mu}M resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR. - Graphical abstract: Display Omitted Highlights: > Effects of plant polyphenols on inflammatory responses in human keratinocytes. > Inflammatory stimuli used: TGFalpha, TNFalpha+IFNgamma, UVA+UVB, and LPS. > Inflammatory pathways connected with NFB, ERK1/2, EGFR, and AhR were investigated. > Plant polyphenols, flavonoids, stilbenoids, and phenylpropanoids, were studied. > Modulation of inflammation depends on phenolic core structure and glycosylation.

Potapovich, Alla I. [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Biology Department, Belarus State University, Skorina Prosp. 10, Minsk 220050 (Belarus); Lulli, Daniela; Fidanza, Paolo [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Kostyuk, Vladimir A. [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Biology Department, Belarus State University, Skorina Prosp. 10, Minsk 220050 (Belarus); De Luca, Chiara; Pastore, Saveria [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Korkina, Liudmila G., E-mail: l.korkina@idi.it [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy)

2011-09-01

114

Inhibition of transcription factor specificity protein 1 alters the gene expression profile of keratinocytes leading to upregulation of kallikrein-related peptidases and thymic stromal lymphopoietin.  

PubMed

Transcription factor specificity protein 1 (Sp1) is involved in diverse cellular functions. We recently found that Sp1 was significantly decreased in skin biopsy samples obtained from patients with atopic dermatitis (AD) and had an even greater reduction in AD patients with a history of eczema herpeticum. In the current study, we sought to better understand the role of Sp1 in skin biological processes by using a small-interfering RNA (siRNA) technique to knock down Sp1 gene expression in normal human keratinocytes (NHKs) and investigated the genome-wide gene expression profiling of Sp1-silenced NHKs. The gene arrays revealed that 53 genes had greater than 3-fold changes in the expression in Sp1-silenced NHKs as compared with scrambled siRNA-silenced cells. Strikingly, six kallikrein (KLK)-related peptidase genes, namely KLK5, KLK6, KLK7, KLK8, KLK10, and KLK12, were upregulated in NHKs following Sp1 silencing. Functionally, protease activity was significantly enhanced in Sp1-silenced keratinocytes as compared with scrambled siRNA-silenced keratinocytes. Moreover, thymic stromal lymphopoietin (TSLP), an epithelial-derived T(H)2-promoting cytokine, was induced in Sp1-silenced keratinocytes because of elevated KLK activity. These results indicate that Sp1 expression deficiency leads to abnormally increased KLK protease activity in keratinocytes and may contribute to T(H)2 immune responses in the skin by inducing TSLP. PMID:21753780

Bin, Lianghua; Kim, Byung E; Hall, Clifton F; Leach, Sonia M; Leung, Donald Y M

2011-11-01

115

Human keratinocytes are a source for tumor necrosis factor alpha: Evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light  

Microsoft Academic Search

Tumor necrosis factor alpha (TNF-alpha), in addition to being cytotoxic for certain tumor cells, has turned out as a multifunctional cytokine that is involved in the regulation of immunity and inflammation. Since human keratinocytes have been demonstrated to be a potent source of various cytokines, it was investigated whether epidermal cells synthesize and release TNF-alpha. Supernatants derived from normal human

A. S. Koeck; T. Schwarz; R. Kirnbauer; A. Urbanski; P. Perry; J. C. Ansel; T. A. Luger

1990-01-01

116

Ectopic Expression of Syndecan-1 in Basal Epidermis Affects Keratinocyte Proliferation and Wound Re-Epithelialization  

Microsoft Academic Search

Epidermal proliferation and differentiation can be regulated by soluble morphogens and growth factors. Heparan sulfate proteoglycans (HSPGs) modulate the action of several of these effector molecules, such as members of the fibroblast growth factor (FGF) and Wnt families. Syndecan-1 is a cell-surface proteoglycan that is expressed in differentiating keratinocytes and transiently upregulated in all layers of the epidermis upon tissue

Nkemcho Ojeh; Katri Hiilesvuo; Anni Wärri; Markku Salmivirta; Tiina Henttinen; Arto Määttä

2008-01-01

117

ASSOCIATION BETWEEN PSORIASIS SEVERITY AND TRANSFORMING GROWTH FACTOR ? 1 AND ? 2 IN PLASMA AND SCALES FROM PSORIATIC LESIONS  

Microsoft Academic Search

Psoriasis is an inflammatory skin disorder with hyperproliferation of keratinocytes, that can be the result of insufficient inhibitory effect of transforming growth factors-? (TGF-?). The aim of this study was to evaluate an association between TGF-?1 and -?2 in plasma or scales from psoriatic lesions and the severity of the disease. TGF-? concentrations were measured with an enzyme immunoassay in

Iwona Flisiak; Bo?ena Chodynicka; Piotr Porebski; Robert Flisiak

2002-01-01

118

Expression of the retinoid-inducible polypeptide, midkine, in human epidermal keratinocytes  

Microsoft Academic Search

Midkine (MK) is a retinoid-inducible and potent cell growth\\/differentiation factor active during mouse embryogenesis. We\\u000a studied MK expression in various cell strains established from the skin. MK and its mRNA were detected in cultured keratinocytes\\u000a but not in melanoma cell lines or dermal fibroblasts by both Western blot analysis and reverse transcription-polymerase chain\\u000a reaction (RT-PCR). Treatment of cultured keratinocytes with

Toyoko Inazumi; Shingo Tajima; Takeji Nishikawa; Kenji Kadomatsu; Hisako Muramatsu; Takashi Muramatsu

1997-01-01

119

Oncogenes, genes, and growth factors  

SciTech Connect

This book contains 12 chapters. Some of the chapter titles are: The Epidermal Growth Factor Receptor Gene; Structure and Expression of the Nerve Growth Factor Gene; The Erythropoietin Gene; The Interleukin-2 Gene; The Transferrin Gene; and The Transferrin Receptor Gene.

Guroff, G.

1989-01-01

120

Keratinocytes promote proliferation and inhibit apoptosis of the underlying fibroblasts: an important role in the pathogenesis of keloid.  

PubMed

Interactions between epidermal keratinocytes and dermal fibroblasts play an important role in regulating tissue homeostasis and repair. Nevertheless, little is known about the role of keratinocytes in the pathogenesis of keloid. In this study, we investigated the influence of normal skin- and keloid-derived keratinocytes on normal skin- and keloid-derived fibroblasts utilizing a serum-free indirect coculture system. The keloid-derived fibroblasts showed a greater proliferation and minimal apoptosis when cocultured with normal skin- or keloid-derived keratinocytes, and the results were most significant in the latter. This difference was not observed when the fibroblasts were treated with conditioned medium obtained from normal skin- and keloid-derived keratinocytes. Nevertheless, conditioned medium-treated groups showed more proliferation and less apoptosis compared to the nonconditioned medium-treated control groups. We also analyzed the profile of factors involved in cell growth and apoptosis in fibroblasts cocultured with keratinocytes. Extracellular signal-regulated kinase and c-Jun N-terminal kinase phosphorylations and expression of Bcl-2 and transforming growth factor-beta1 were all significantly upregulated in the fibroblasts cocultured with keloid-derived keratinocytes. Together, these results strongly suggest that the overlying keratinocytes of the keloid lesion play an important role in keloidogenesis by promoting more proliferation and less apoptosis in the underlying fibroblasts through paracrine and double paracrine effects. PMID:14675177

Funayama, Emi; Chodon, Thinle; Oyama, Akihiko; Sugihara, Tsuneki

2003-12-01

121

Id1 and NF-?B promote the generation of CD133+ and BMI-1+ keratinocytes and the growth of xenograft tumors in mice  

PubMed Central

Id1 and NF-?B are highly expressed in oral squamous cell carcinoma (OSCC). Whether they have a synergistic role in the carcinogenesis of OSCC is unclear. The current study was designed to demonstrate the synergy of both Id1 and NF-?B in the underlying disease mechanisms of OSCC using in vitro and in vivo animal models. Id1 and NF-?B strengthened the expression of both CD133 and BMI-1 in OSCC cell cultures. CD133+ and BMI-1+ keratinocytes from OSCC tissues and cell cultures initiated the growth of xenograft tumors in SCID/Beige mice. Id1 and NF-?B regulate the expression of CD133 and BMI-1 in an additive or synergistic manner in OSCC, which is associated with the generation of naïve and self-renewable keratinocytes and initiate the growth of xenograft tumors in vivo. PMID:24572994

LAI, JINHUO; CAI, QIAN; BIEL, MERRILL A.; WANG, CHUAN; HU, XIAOHUA; WANG, SHAOYUAN; LIN, JIZHEN

2014-01-01

122

p300 Alters Keratinocyte Cell Growth and Differentiation through Regulation of p21Waf1/CIP1  

PubMed Central

Background p300 functions as a transcriptional co-activator to regulate many cellular responses such as cell growth, transformation, development and differentiation. It has been shown to affect the transcriptional activity of p53 which regulates p21Waf1/CIP1 expression, however, the role of p300 in differentiation remains unclear. Methodology and Principal Findings Knockdown of p300 protein with short hairpin RNA (shRNA) molecules delays human neonatal foreskin keratinocyte (HFKs) differentiation. Moreover, depletion of p300 increases the proliferative capacity of HFKs, extends the life span of cells and allows differentiated HFKs to re-enter the cell cycle. Studies indicate that depletion of p300 down-regulates the acetylation and expression of p53, and chromatin immunoprecipitation (ChIP) analysis shows that induction of p21Waf1/CIP1 in early differentiation is a result of p300 dependent activation of p53 and that depletion of p21Waf1/CIP1 results in the delay of differentiation and a phenotype similar to p300 depletion. Conclusions p300 has a direct role in the control of cell growth and differentiation in primary epithelial cells, and p21Waf1/CIP1 is an important mediator of these p300 functions. PMID:20084294

Wong, Ping-Pui; Pickard, Adam; McCance, Dennis J.

2010-01-01

123

Mouse fibroblast growth factor 10: cDNA cloning, protein characterization, and regulation of mRNA expression  

Microsoft Academic Search

Fibroblast growth factor 7 (FGF-7) or keratinocyte growth factor (KGF), is a potent and specific mitogen for epithelial cells. We have recently identified a novel human FGF-7 homologue, named FGF-10.To study the expression of this new FGF family member and its regulation in wound repair, we cloned the mouse FGF-10 (mFGF-10) cDNA. The encoded protein is 92% identical to human

Hans-Dietmar Beer; Charles Florence; Johanna Dammeier; Linda McGuire; Sabine Werner; D Roxanne Duan

1997-01-01

124

Interferon regulatory factor (IRF)-2 activates the HPV-16 E6-E7 promoter in keratinocytes.  

PubMed

Interferon regulatory factors (IRFs) are critical mediators of gene expression, cell growth and immune responses. We previously demonstrated that interferon (IFN) induction of early viral transcription and replication in several mucosal HPVs requires IRF-1 binding to a conserved interferon response element (IRE). Here we show that the IRF-2 protein serves as a baseline transactivator of the HPV-16 major early promoter, P97. Cotransfections in IRF knockout cells confirmed that basal HPV-16 promoter activity was supported by both IRF-1 and IRF-2 complexes interacting with the promoter-proximal IRE in a dose-dependent manner. Furthermore, HPV-16 E7 expression downregulates the IRF-2 promoter, thus linking IRF-2 levels to viral transforming gene expression through a negative feedback mechanism. Taken together, these observations reveal a complex viral strategy utilizing multiple signal transduction pathways during the establishment and maintenance of HPV persistence. PMID:20129639

Lace, Michael J; Anson, James R; Haugen, Thomas H; Turek, Lubomir P

2010-04-10

125

Different Pathways Are Involved in Arsenic-Trioxide-Induced Cell Proliferation and Growth Inhibition in Human Keratinocytes  

Microsoft Academic Search

Background: Arsenic is a carcinogen that is associated with an increased risk of human skin cancer. On the other hand, arsenic trioxide (As2O3) has potential anticancer activity against a wide range of carcinomas. The mechanisms involved in these two opposing processes remain unclear. Methods: We used normal human keratinocytes (NHK), the human keratinocyte HaCaT cell line and human epidermal carcinoma

X. Bi; J. Gu; Z. Guo; S. Tao; Y. Wang; L. Tang; J. Wu; Q. Mi

2010-01-01

126

Interstitial fibrosis and growth factors.  

PubMed Central

Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy. Our laboratory has focused on the molecular mechanisms through which three selected peptide growth factors could play a role in the development of IPF. Hundreds of growth factors and cytokines could be involved in the complex disease process. We are studying platelet-derived growth factor because it is the most potent mesenchymal cell mitogen yet described, transforming growth factor beta because it is a powerful inducer of extracellular matrix (scar tissue) components by mesenchymal cells, and tumor necrosis factor alpha because it is a pleiotropic cytokine that we and others have shown is essential for the development of IPF in animal models. This review describes some of the evidence from studies in humans, in animal models, and in vitro, that supports the growth factor hypothesis. The use of modern molecular and transgenic technologies could elucidate those targets that will allow effective therapeutic approaches. Images Figure 1 Figure 2 PMID:10931794

Lasky, J A; Brody, A R

2000-01-01

127

Growth factors in ischemic stroke  

PubMed Central

Abstract Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1? and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects. PMID:20015202

Lanfranconi, S; Locatelli, F; Corti, S; Candelise, L; Comi, G P; Baron, P L; Strazzer, S; Bresolin, N; Bersano, A

2011-01-01

128

An unbiased in vivo screen reveals multiple transcription factors that control HPV E6-regulated hTERT in keratinocytes  

PubMed Central

Activation of telomerase by human papillomavirus 16 (HPV16) E6 is a critical step for cell immortalization and transformation in human foreskin keratinocytes (HFKs). Multiple transcription factors have been identified as being involved in E6-induced hTERT expression. Here, we adapted an unbiased in vivo screen using a LacO-LacI system in human cells to discover hTERT promoter-interacting regulators. This approach allowed us to identify a novel hTERT repressor, Maz, which bound the hTERT promoter. E6 expression reduced Maz binding and correspondingly increased Sp1 binding at the hTERT promoter. Knockdown of Maz further increased histone acetylation, as well as hTERT expression in the presence of E6. Overall, these data indicate the utility of a novel screen for promoter-interacting and transcription-regulating proteins. These data also highlight multiple factors that normally regulate hTERT repression in HFKs, and therefore are targeted by E6 for hTERT expression. PMID:24074563

Xu, Mei; Katzenellenbogen, Rachel A.; Grandori, Carla; Galloway, Denise A.

2013-01-01

129

Platelet-Derived Growth Factor-BB Controls Epithelial Tumor Phenotype by Differential Growth Factor Regulation in Stromal Cells  

PubMed Central

Platelet-derived growth factor (PDGF) stimulates tumor growth and progression by affecting tumor and stromal cells. In the HaCaT skin carcinogenesis model, transfection of immortal nontumorigenic and PDGF-receptor-negative HaCaT keratinocytes with PDGF-B induced formation of benign tumors. Here, we present potential mechanisms underlying this tumorigenic conversion. In vivo, persistent PDGF-B expression induced enhanced tumor cell proliferation but only transiently stimulated stromal cell proliferation and angiogenesis. In vitro and in vivo studies identified fibroblasts as PDGF target cells essential for mediating transient angiogenesis and persistent epithelial hyperproliferation. In fibroblast cultures, long-term PDGF-BB treatment caused an initial up-regulation of vascular endothelial growth factor (VEGF)-A, followed by a drastic VEGF down-regulation and myofibroblast differentiation. Accordingly, in HaCaT/PDGF-B transplants, initially enhanced VEGF expression by stromal fibroblasts was subsequently reduced, followed by down-regulation of angiogenesis, myofibroblast accumulation, and vessel maturation. The PDGF-induced, persistently increased expression of the hepatocyte growth factor by fibroblasts in vitro and in vivo was most probably responsible for enhanced epithelial cell proliferation and benign tumor formation. Thus, by paracrine stimulation of the stroma, PDGF-BB induced epithelial hyperproliferation, thereby promoting tumorigenicity, whereas the time-limited activation of the stroma followed by stromal maturation provides a possible explanation for the benign tumor phenotype. PMID:17071599

Lederle, Wiltrud; Stark, Hans-Jürgen; Skobe, Mihaela; Fusenig, Norbert E.; Mueller, Margareta M.

2006-01-01

130

Role of p12(CDK2-AP1) in transforming growth factor-beta1-mediated growth suppression.  

PubMed

p12(CDK2-AP1) (p12) is a growth suppressor isolated from normal keratinocytes. Ectopic expression of p12 in squamous carcinoma cells reversed the malignant phenotype of these cells, in part due an ability of p12 to bind to both DNA polymerase alpha/primase and to cyclin-dependent kinase 2 (CDK2), thereby inhibiting their activities. We report in this article that in normal epithelial cells, transforming growth factor beta1 (TGF-beta1) induces p12 expression transcriptionally, which, in turn, mediates the growth inhibitory activity of TGF-beta1. We created inducible p12 antisense HaCaT cell lines [ip12 (-) HaCaT] and showed that selective reduction of cellular p12 resulted in an increase in: (a) CDK2-associated kinase activity; (b) protein retinoblastoma (pRB) phosphorylation; and (c) [(3)H]thymidine incorporation, and partially reversed TGF-beta1-mediated inhibition of CDK2 kinase activity, pRB phosphorylation, and cell proliferation. Furthermore, we generated p12-deficient mouse oral keratinocytes (MOK(p12-/-)) and compared their growth characteristics and response to TGF-beta1 with that of wild-type mouse oral keratinocytes (MOK(WT)). Under normal culture conditions, the number of MOK(p12-/-) in S phase is 2-fold greater than that of MOK(WT). Concomitantly, fewer cells are in G(2) phase in MOK(p12-/-) than that in MOK(WT). Moreover, response to TGF-beta1-mediated growth suppression is compromised in MOK(p12-/-) cells. Mechanistic studies showed that MOK(p12-/-) have increased CDK2 activity and reduced sensitivity to inhibition by TGF-beta1. Collectively our data suggest that p12 plays a role in TGF-beta1-mediated growth suppression by modulating CDK2 activities and pRB phosphorylation. PMID:14744761

Hu, Miaofen G; Hu, Guo-Fu; Kim, Yong; Tsuji, Takanori; McBride, Jim; Hinds, Philip; Wong, David T W

2004-01-15

131

Effects of Cerium Oxide Nanoparticles on the Growth of Keratinocytes, Fibroblasts and Vascular Endothelial Cells in Cutaneous Wound Healing  

PubMed Central

Rapid and effective wound healing requires a coordinated cellular response involving fibroblasts, keratinocytes and vascular endothelial cells (VECs). Impaired wound healing can result in multiple adverse health outcomes and, although antibiotics can forestall infection, treatments that accelerate wound healing are lacking. We now report that topical application of water soluble cerium oxide nanoparticles (Nanoceria) accelerates the healing of full-thickness dermal wounds in mice by a mechanism that involves enhancement of the proliferation and migration of fibroblasts, keratinocytes and VECs. The Nanoceria penetrated into the wound tissue and reduced oxidative damage to cellular membranes and proteins, suggesting a therapeutic potential for topical treatment of wounds with antioxidant nanoparticles. PMID:23266256

Chigurupati, Srinivasulu; Mughal, Mohamed R.; Okun, Eitan; Das, Soumen; Kumar, Amit; McCaffery, Michael; Seal, Sudipta; Mattson, Mark P.

2012-01-01

132

Calcipotriol Affects Keratinocyte Proliferation by Decreasing Expression of Early Growth Response1 and Polo-like Kinase2  

Microsoft Academic Search

Purpose  Calcipotriol is a potent drug for topical treatment of psoriasis because it manages to inhibit keratinocyte proliferation.\\u000a In the present study we investigated the effects of calcipotriol on gene expression in human keratinocytes in terms of mechanism\\u000a of how calcipotriol decreases proliferation.\\u000a \\u000a \\u000a \\u000a Materials and methods  Cell proliferation was analyzed by MTT assay. The differential display approach together with qPCR was used

Jernej Kristl; Petra Slanc; Metka Krašna; Aleš Berlec; Matjaž Jeras; Borut Štrukelj

2008-01-01

133

Epidermal growth factor: layered silicate nanocomposites for tissue regeneration.  

PubMed

Wound healing is a complex, multistep process that can be summarized into three stages, namely, hemostasis and inflammation, proliferation, and finally, tissue remodeling. Battlefield wound healing demands rapid hemostasis using clotting or cauterizing agents to immediately limit blood loss, but this occurs at the expense of proper tissue repair beyond hemostasis. Layered silicate clays such as kaolin and montmorillonite (MMT) have been previously shown to induce blood clotting due to their ability to form charged interactions with clotting factors. The charge characteristics of sodium MMT (Na-MMT) also enable functionalization with active biomolecules. Herein we functionalized Na-MMT with epidermal growth factor (EGF) via ion exchange reaction to create a nanocomposite (MMT-EGF) with approximately 0.004 EGF molecules per Na(+) exchange site and conduct biochemical analyses of keratinocytes after treatment with MMT-EGF. Our results demonstrate that EGF immobilized on MMT retains the ability to activate the epidermal growth factor receptor (EGRF), causing phosphorylation of the AKT and MEK1 pathways, as well as upregulation of its downstream target gene expression involved in cell growth and migration. This study also shows that like EGF, MMT-EGF treatment can stimulate cell migration in vitro, which is dependent on ERK1/2 phosphorylation. PMID:21766827

Vaiana, Christopher A; Leonard, Mary K; Drummy, Lawrence F; Singh, Kristi M; Bubulya, Athanasios; Vaia, Richard A; Naik, Rajesh R; Kadakia, Madhavi P

2011-09-12

134

Angiogenic growth factors and hypertension  

Microsoft Academic Search

Emerging evidence supports a novel view of hypertension as a disease of inadequate or aberrant responses to angiogenic growth factors (AGF). Patients with hypertension have reduced microvascular density, with some evidence supporting a primary role for rarefaction in causing hypertension. Two clinical models have demonstrated a link between inhibition of AGF activity and hypertension. A major side effect of bevacizumab,

David C. Sane; Lauren Anton; K. Bridget Brosnihan

2004-01-01

135

Growth factors in orthopedic surgery  

PubMed Central

Growth factors have represented an essential issue of interest for the researchers and clinicians in orthopedics and trauma over the last 40 years. In the last 10 to 15 years, the advances registered in this field have permitted the identification of the most active cellular and humoral factors as well as the improvement of their use in the orthopedic and trauma surgery. Their domain of application has been continuously enlarged and the results have been visible from the beginning. The authors present their appreciation on the actual state of this subject as well as their experience with results and related conclusions. PMID:20302195

Zaharia, C; Despa, N; Simionescu, M; Jinga, V; Fleseriu, I

2010-01-01

136

Transcription factor Nrf2 activation by inorganic arsenic in cultured keratinocytes: involvement of hydrogen peroxide  

Microsoft Academic Search

Inorganic arsenic is a well-documented human carcinogen that targets the skin. The induction of oxidative stress, as shown with arsenic, may have a bearing on the carcinogenic mechanism of this metalloid. The transcription factor Nrf2 is a key player in the regulation of genes encoding for many antioxidative response enzymes. Thus, the effect of inorganic arsenic (as sodium arsenite) on

Jingbo Pi; Wei Qu; Jeffrey M Reece; Yoshito Kumagai; Michael P Waalkes

2003-01-01

137

Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors  

PubMed Central

Although numerous epidemiological studies have shown that inorganic arsenicals cause skin cancers and hyperkeratoses in humans, there are currently no established mechanisms for their action or animal models. Previous studies in our laboratory using primary human keratinocyte cultures demonstrated that micromolar concentrations of inorganic arsenite increased cell proliferation via the production of keratinocyte-derived growth factors. As recent reports demonstrate that overexpression of keratinocyte-derived growth factors, such as transforming growth factor (TGF)-?, promote the formation of skin tumors, we hypothesized that similar events may be responsible for those associated with arsenic skin diseases. Thus, the influence of arsenic in humans with arsenic skin disease and on mouse skin tumor development in transgenic mice was studied. After low-dose application of tetradecanoyl phorbol acetate (TPA), a marked increase in the number of skin papillomas occurred in Tg.AC mice, which carry the v-Ha-ras oncogene, that received arsenic in the drinking water as compared with control drinking water, whereas no papillomas developed in arsenic-treated transgenic mice that did not receive TPA or arsenic/TPA-treated wild-type FVB/N mice. Consistent with earlier in vitro findings, increases in granulocyte/macrophage colony-stimulating factor (GM-CSF) and TGF-? mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment. Immunohistochemical staining localized TGF-? overexpression to the hair follicles. Injection of neutralizing antibodies to GM-CSF after TPA application reduced the number of papillomas in Tg.AC mice. Analysis of gene expression in samples of skin lesions obtained from humans chronically exposed to arsenic via their drinking water also showed similar alterations in growth factor expression. Although confirmation will be required in nontransgenic mice, these results suggest that arsenic enhances development of skin neoplasias via the chronic stimulation of keratinocyte-derived growth factors and may be a rare example of a chemical carcinogen that acts as a co-promoter. PMID:9846968

Germolec, Dori R.; Spalding, Judson; Yu, Hsin-Su; Chen, G. S.; Simeonova, Petia P.; Humble, Michael C.; Bruccoleri, Alessandra; Boorman, Gary A.; Foley, Julie F.; Yoshida, Takahiko; Luster, Michael I.

1998-01-01

138

Exogenous Fibroblast Growth Factor10 Induces Cystic Lung Development with Altered Target Gene Expression in the Presence of Heparin in Cultures of Embryonic Rat Lung  

Microsoft Academic Search

Objectives: Signaling by fibroblast growth factor (FGF) receptor (FGFR) 2IIIb regulates branching morphogenesis in the mammalian lung. FGFR2IIIb is primarily expressed in epithelial cells, whereas its ligands, FGF-10 and keratinocyte growth factor (KGF; FGF-7), are expressed in mesenchymal cells. FGF-10 null mice lack lungs, whereas KGF null animals have normal lung development, indicating that FGF-10 regulates lung branching morphogenesis. In

Shuichi Hashimoto; Hiroshi Nakano; Yuko Suguta; Seiko Irie; Luo Jianhua; Sikardar L. Katyal

2012-01-01

139

Transduction of the E6 and E7 genes of epidermodysplasia-verruciformis-associated human papillomaviruses alters human keratinocyte growth and differentiation in organotypic cultures.  

PubMed

Epidermodysplasia-verruciformis-associated human papilloma virus DNA has been detected in skin cancers, in premalignant and benign skin lesions, and in plucked hairs from immunocompetent and immunosuppressed patients. The role of epidermodysplasia-verruciformis-associated human papilloma virus in the pathogenesis of nonmelanoma skin cancer is still enigmatic. In organotypic cultures we investigated the effects of retroviral transduction of the E6 and E7 genes of epidermodysplasia-verruciformis-associated human papilloma virus types 5, 12, 15, 17, 20, and 38 on the growth and differentiation of human keratinocytes. Differentiation was disturbed to different degrees as revealed by histology and by the expression patterns of differentiation markers keratin 10 and small proline rich protein 2. Conversely, proliferating cell nuclear antigen was induced in some of the suprabasal, differentiated cells to varying extent. No unscheduled DNA synthesis was detected in these cells, however, as probed by 5'-bromo-2'-deoxyuridine incorporation. Most intriguingly, when the E6 and E7 genes of epidermodysplasia-verruciformis-associated human papilloma virus types 15 and 17 were transduced, a broadening layer of basal cells and an accelerated differentiation were observed. In addition, "papilla-like structures" comprising basal-like keratinocytes arose from the basal layer into the differentiated layers. These cells did not express the differentiation markers keratin 10 and small proline rich protein 2, but did actively replicate DNA. These observations warrant further research by using this system to elucidate the replication strategy of epidermodysplasia-verruciformis-associated human papilloma virus types in keratinocytes and to shed light on the role of these human papilloma virus types in the pathogenesis of skin cancer. PMID:11886500

Boxman, I L; Mulder, L H; Noya, F; de Waard, V; Gibbs, S; Broker, T R; ten Kate, F; Chow, L T; ter Schegget, J

2001-12-01

140

Cyclic stretch induces upregulation of endothelin-1 with keratinocytes in vitro: Possible role in mechanical stress-induced hyperpigmentation  

SciTech Connect

Highlights: {yields} Influence of cyclic stretch on melanogenetic paracrine cytokines was investigated. {yields} Keratinocyte-derived endothelin-1 was upregulated with cyclic stretch. {yields} Degree of upregulation increases dose-dependently. {yields} This upregulation possibly plays a role in the pathogenesis of pigmented disorders. -- Abstract: The aim of this study was to investigate the possible pathological relation between mechanical stress and hyperpigmentation. We did this by investigating the influence of cyclic stretch on the expression of keratinocyte- and fibroblast-derived melanogenetic paracrine cytokines in vitro. Using primary human keratinocytes and fibroblasts, alterations of mRNA expression of melanogenetic paracrine cytokines due to cyclic stretch were investigated using a real-time polymerase chain reaction (PCR). The cytokines included basic fibroblast growth factor (bFGF), stem cell factor (SCF), granulocyte/macrophage colony-stimulating factor, interleukin-1{alpha}, and endothelin-1 (ET-1) for keratinocytes and bFGF, SCF, and hepatocyte growth factor for fibroblasts. The dose dependence of keratinocyte-derived ET-1 upregulation was further investigated using real-time PCR and an enzyme-linked immunosorbent assay. We also investigated the effects of cyclic stretch on the proliferation and differentiation of keratinocytes. Among the melanogenetic paracrine cytokines investigated, keratinocyte-derived ET-1 was consistently upregulated in all four cell lines. The degree of upregulation increased with the degree of the length and frequency of the stretch; in contrast, cell number and differentiation markers showed no obvious alterations with cyclic stretch. Keratinocyte-derived ET-1 upregulation possibly plays a significant role in the pathogenesis of pigmented disorders, such as friction melanosis, caused by mechanical stress.

Kurita, Masakazu, E-mail: masakazukurita@gmail.com [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)] [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Okazaki, Mutsumi [Department of Plastic and Reconstructive Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan)] [Department of Plastic and Reconstructive Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Fujino, Takashi [Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)] [Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Takushima, Akihiko; Harii, Kiyonori [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)] [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)

2011-05-27

141

Expression of basic fibroblast growth factor (bFGF) in Kaposi's sarcoma: an immunohistologic study.  

PubMed

Ten cases of Kaposi's sarcoma (KS) including five AIDS-KS, one classical KS, and four pseudo-KS (acroangiodermatitis) were investigated for their expression of basic fibroblast growth factor. Antigen expression was demonstrated by immunoperoxidase staining of cryostat sections with affinity-purified anti-bFGF antibodies. It was found that bFGF was strongly expressed in basal and suprabasal keratinocytes, which were also intensively stained in normal skin biopsies. The growth factor was generally absent from the endothelial cells and spindle cells of the neoplasms. These cell types exhibited a very faint staining in a small number of lesions. The studies provide strong evidence that proliferation of KS tumor cells may not be explained by autocrine secretion mechanism of the growth factor, which has been suggested in previous reports with in vitro cultured KS cell lines. PMID:2199583

Schulze-Osthoff, K; Goerdt, S; Sorg, C

1990-08-01

142

Biochemical and functional analysis of smallpox growth factor (SPGF) and anti-SPGF monoclonal antibodies.  

PubMed

Variola, the causative agent of smallpox, is a highly infectious double-stranded DNA virus of the orthopox genus that replicates within the cytoplasm of infected cells. For unknown reasons prominent skin manifestations, including "pox," mark the course of this systemic human disease. Here we characterized smallpox growth factor (SPGF), a protein containing an epidermal growth factor (EGF)-like domain that is conserved among orthopox viral genomes, and investigated its possible mechanistic link. We show that after recombinant expression, refolding, and purification, the EGF domain of SPGF binds exclusively to the broadly expressed cellular receptor, erb-B1 (EGF receptor), with subnanomolar affinity, stimulating the growth of primary human keratinocytes and fibroblasts. High affinity monoclonal antibodies specific for SPGF reveal in vivo immunoprotection in a murine vaccinia pneumonia model by a mechanism distinct from viral neutralization. These findings suggest that blockade of pathogenic factor actions, in general, may be advantageous to the infected host. PMID:15070899

Kim, Mikyung; Yang, Hailin; Kim, Sung-Kwon; Reche, Pedro A; Tirabassi, Rebecca S; Hussey, Rebecca E; Chishti, Yasmin; Rheinwald, James G; Morehead, Tiara J; Zech, Tobias; Damon, Inger K; Welsh, Raymond M; Reinherz, Ellis L

2004-06-11

143

Fetal fibroblasts and keratinocytes with immunosuppressive properties for allogeneic cell-based wound therapy.  

PubMed

Fetal skin heals rapidly without scar formation early in gestation, conferring to fetal skin cells a high and unique potential for tissue regeneration and scar management. In this study, we investigated the possibility of using fetal fibroblasts and keratinocytes to stimulate wound repair and regeneration for further allogeneic cell-based therapy development. From a single fetal skin sample, two clinical batches of keratinocytes and fibroblasts were manufactured and characterized. Tolerogenic properties of the fetal cells were investigated by allogeneic PBMC proliferation tests. In addition, the potential advantage of fibroblasts/keratinocytes co-application for wound healing stimulation has been examined in co-culture experiments with in vitro scratch assays and a multiplex cytokines array system. Based on keratin 14 and prolyl-4-hydroxylase expression analyses, purity of both clinical batches was found to be above 98% and neither melanocytes nor Langerhans cells could be detected. Both cell types demonstrated strong immunosuppressive properties as shown by the dramatic decrease in allogeneic PBMC proliferation when co-cultured with fibroblasts and/or keratinocytes. We further showed that the indoleamine 2,3 dioxygenase (IDO) activity is required for the immunoregulatory activity of fetal skin cells. Co-cultures experiments have also revealed that fibroblasts-keratinocytes interactions strongly enhanced fetal cells secretion of HGF, GM-CSF, IL-8 and to a lesser extent VEGF-A. Accordingly, in the in vitro scratch assays the fetal fibroblasts and keratinocytes co-culture accelerated the scratch closure compared to fibroblast or keratinocyte mono-cultures. In conclusion, our data suggest that the combination of fetal keratinocytes and fibroblasts could be of particular interest for the development of a new allogeneic skin substitute with immunomodulatory activity, acting as a reservoir for wound healing growth factors. PMID:23894651

Zuliani, Thomas; Saiagh, Soraya; Knol, Anne-Chantal; Esbelin, Julie; Dréno, Brigitte

2013-01-01

144

IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes.  

PubMed

While the pro-differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal development, is induced in differentiation through a Notch-dependent mechanism and is a primary Notch target in keratinocytes and keratinocyte-derived SCC cells. Increased IRF6 expression contributes to the impact of Notch activation on growth/differentiation-related genes, while it is not required for induction of 'canonical' Notch targets like p21(WAF1/Cip1), Hes1 and Hey1. Down-modulation of IRF6 counteracts differentiation of primary human keratinocytes in vitro and in vivo, promoting ras-induced tumour formation. The clinical relevance of these findings is illustrated by the strikingly opposite pattern of expression of Notch1 and IRF6 versus epidermal growth factor receptor in a cohort of clinical SCCs, as a function of their grade of differentiation. Thus, IRF6 is a primary Notch target in keratinocytes, which contributes to the role of this pathway in differentiation and tumour suppression. PMID:21909072

Restivo, Gaetana; Nguyen, Bach-Cuc; Dziunycz, Piotr; Ristorcelli, Elodie; Ryan, Russell J H; Özuysal, Özden Yalçin; Di Piazza, Matteo; Radtke, Freddy; Dixon, Michael J; Hofbauer, Günther F L; Lefort, Karine; Dotto, G Paolo

2011-11-16

145

Proteomic Profiling of Human Keratinocytes Undergoing UVB-Induced Alternative Differentiation Reveals TRIpartite Motif Protein 29 as a Survival Factor  

Microsoft Academic Search

BackgroundRepeated exposures to UVB of human keratinocytes lacking functional p16INK-4a and able to differentiate induce an alternative state of differentiation rather than stress-induced premature senescence.Methodology\\/Principal FindingsA 2D-DIGE proteomic profiling of this alternative state of differentiation was performed herein at various times after the exposures to UVB. Sixty-nine differentially abundant protein species were identified by mass spectrometry, many of which are

Véronique Bertrand-Vallery; Nathalie Belot; Marc Dieu; Edouard Delaive; Noëlle Ninane; Catherine Demazy; Martine Raes; Michel Salmon; Yves Poumay; Florence Debacq-Chainiaux; Olivier Toussaint; Christophe Egles

2010-01-01

146

3D co-cultures of keratinocytes and melanocytes and cytoprotective effects on keratinocytes against reactive oxygen species by insect virus-derived protein microcrystals.  

PubMed

Stable protein microcrystals called polyhedra are produced by certain insect viruses. Cytokines, such as fibroblast growth factors (FGFs), can be immobilized within polyhedra. Here, we investigated three-dimensional (3D) co-cultures of keratinocytes and melanocytes on collagen gel containing FGF-2 and FGF-7 polyhedra. Melanocytes were observed to reside at the base of the 3D cell culture and melanin was also typically observed in the lower layer. The 3D cell culture model with FGF-2 and FGF-7 polyhedra was a useful in vitro model of the epidermis due to effective melanogenesis, proliferation and differentiation of keratinocytes. FGF-7 polyhedra showed a potent cytoprotective effect when keratinocytes were treated with menadione, which is a generator of reactive oxygen species. The cytoprotective effect was activated by the inositol triphosphate kinase-Akt pathway leading to upregulation of the antioxidant enzymes superoxide dismutase and peroxiredoxin 6. PMID:25063093

Shimabukuro, Junji; Yamaoka, Ayako; Murata, Ken-Ichi; Kotani, Eiji; Hirano, Tomoko; Nakajima, Yumiko; Matsumoto, Goichi; Mori, Hajime

2014-09-01

147

Xenobiotics in vitro: the influence of L-cystine, pantothenat, and miliacin on metabolic and proliferative capacity of keratinocytes.  

PubMed

To investigate the effect of cell growth-stimulating agents on human epidermal keratinocytes, we exposed monolayers of normal human keratinocytes derived from foreskin to different concentrations of the amino acid L-cystine, the member of the vitamin B family D-pantothenat, the phytosterol miliacin, and a combination thereof in keratinocyte growth medium. As a test system for the metabolic capacity, we used the activity of mitochondrial deyhdrogenases as measured by XTT, and for the cell proliferation, we determined the BrdU-uptake. The additives, active ingredients of the hair growth drug PRIORIN, were added in the presence of fully supplemented keratinocyte growth medium or a deficient medium without L-cystine, L-methionine, L-histidin, D-pantothenat, epidermal growth factor, and bovine pituary gland extract. Deficient medium itself reduced the metabolic capacity of keratinocytes to 35% compared with keratinocytes in fully supplemented growth medium. In deficient medium cell, proliferation was not measurable. Increasing doses of L-cystine restored the reduced metabolic capacity from 46% (0.009 mg/L) to 54% (0.09 mg/L) and 92% (0.45 mg/L) in deficient medium. Addition of D-pantothenat (0.43 mg/L) enhanced the metabolic capacity to 150% only in fully supplemented growth medium, compared with untreated controls with growth medium. Miliacin (6 mg/mL) increased not only the metabolic capacity (162%) but also stimulated cell proliferation (215%) as measured by BrdU-uptake in growth medium. The combination of all three additives increased the metabolic capacity (245%) synergistically in growth medium. We were able to show effects of D-panthenol, L-lysine, and miliacin on proliferation and metabolic capacity of keratinocyte monocell culture, which was further increased by combination of the three substances. These basic results suggest a beneficial effect on keratinocyte growth and stimulation by products combining these substances (e.g., Priorin). Furthermore, this work emphasizes the suitability of keratinocyte monolayers for pharmacological testings. PMID:16702051

Obrigkeit, D Hoeller; Oepen, T; Jugert, F K; Merk, H F; Kubicki, J

2006-01-01

148

Human papillomavirus causes an angiogenic switch in keratinocytes which is sufficient to alter endothelial cell behavior  

SciTech Connect

One of the requirements for tumor growth is the ability to recruit a blood supply, a process known as angiogenesis. Angiogenesis begins early in the progression of cervical disease from mild to severe dysplasia and on to invasive cancer. We have previously reported that expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7) proteins in primary foreskin keratinocytes (HFKs) decreases expression of two inhibitors and increases expression of two angiogenic inducers [Toussaint-Smith, E., Donner, D.B., Roman, A., 2004. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988-2995]. Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation.

Chen, W. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Li, F.; Mead, L.; White, H. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Walker, J. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Ingram, D.A. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Roman, A. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States)], E-mail: aroman@iupui.edu

2007-10-10

149

Arsenite-Mediated Promotion of Anchorage-Independent Growth of HaCaT Cells through Placental Growth Factor.  

PubMed

Various cancers including skin cancer are increasing in 45 million people exposed to arsenic above the World Health Organization's guideline value of 10??g?l(-1). However, there is limited information on key molecules regulating arsenic-mediated carcinogenesis. Our fieldwork in Bangladesh demonstrated that levels of placental growth factor (PlGF) in urine samples from residents of cancer-prone areas with arsenic-polluted drinking water were higher than those in urine samples from residents of an area that was not polluted with arsenic. Our experimental study in human nontumorigenic HaCaT skin keratinocytes showed that arsenite promoted anchorage-independent growth with increased expression and secretion of PlGF, a ligand of vascular endothelial growth factor receptor1 (VEGFR1), and increased VEGFR1/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) activities. The arsenite-mediated promotion of anchorage-independent growth was strongly inhibited by PlGF depletion with decreased activities of the PlGF/VEGFR1/MEK/ERK pathway. Moreover, arsenite proteasome-dependently degrades metal-regulatory transcription factor-1 (MTF-1) protein, resulting in a decreased amount of MTF-1 protein binding to the PlGF promoter. MTF-1 negatively controlled PlGF transcription in HaCaT cells, resulting in increased PlGF transcription. These results suggest that arsenite-mediated MTF-1 degradation enhances the activity of PlGF/VEGFR1/MEK/ERK signaling, resulting in promotion of the malignant transformation of keratinocytes. Thus, this study proposed a molecular mechanism for arsenite-mediated development of skin cancer. PMID:25493652

Yajima, Ichiro; Kumasaka, Mayuko Y; Ohnuma, Shoko; Ohgami, Nobutaka; Naito, Hisao; Shekhar, Hossain U; Omata, Yasuhiro; Kato, Masashi

2015-04-01

150

Growth factors and antimicrobial factors of bovine colostrum  

Microsoft Academic Search

Colostrum is the first natural food produced by female mammals during the first 24–36h directly after giving birth. Chemically, colostrum is a very complex fluid rich in nutrients, antibodies and growth factors. In cows the antibodies provide passive immunity to the new born calf, whereas the growth factors especially stimulate the growth of the gut. The other antimicrobial components of

R. Pakkanen; J. Aalto

1997-01-01

151

Role of Dermatopontin in re-epithelialization: Implications on keratinocyte migration and proliferation  

PubMed Central

Re-epithelialization is a key event in wound healing and any impairment in that process is associated with various pathological conditions. Epidermal keratinocyte migration and proliferation during re-epithelialization is largely regulated by the cytokines and growth factors from the provisional matrix and dermis. Extracellular matrix consists of numerous growth factors which mediate cell migration via cell membrane receptors. Dermatopontin (DPT), a non-collagenous matrix protein highly expressed in dermis is known for its striking ability to promote cell adhesion. DPT also enhances the biological activity of transforming growth factor beta 1 which plays a central role in the process of wound healing. This study was designed to envisage the role of DPT in keratinocyte migration and proliferation along with its mRNA and protein expression pattern in epidermis. The results showed that DPT promotes keratinocyte migration in a dose dependant fashion but fail to induce proliferation. Further, PCR and immunodetection studies revealed that the mRNA and protein expression of DPT is considerably negligible in the epidermis in contrast to the dermis. To conclude, DPT has a profound role in wound healing specifically during re-epithelialization by promoting keratinocyte migration via paracrine action from the underlying dermis. PMID:25486882

Krishnaswamy, Venkat Raghavan; Korrapati, Purna Sai

2014-01-01

152

Growth Factors in Proliferative Diabetic Retinopathy  

PubMed Central

Many growth factors are implicated in the pathogenesis of proliferative diabetic retinopathy. Alteration of growth factors and their receptors in diabetes has been shown in both experimental and clinical studies. Sustained hyperglycemia resulting from long-standing diabetes leads to several biochemical abnormalities that consequently result in retinal hypoxia. Retinal oxygenation state regulates various growth factors that promote angiogenesis in order to meet the oxygen demands of the tissue. However, unregulated expression of these growth factors and induction of complex cascades leading to augmentation of other proangiogenic factors, which may not be regulated by tissue oxygenation, leads to uncontrolled retinal neovascularization and blindness in diabetic patients. PMID:14668050

Khan, Zia Ali

2003-01-01

153

Design and Synthesis of Binding Growth Factors  

PubMed Central

Growth factors play important roles in tissue regeneration. However, because of their instability and diffusible nature, improvements in their performance would be desirable for therapeutic applications. Conferring binding affinities would be one way to improve their applicability. Here we review techniques for conjugating growth factors to polypeptides with particular affinities. Conjugation has been designed at the level of gene fusion and of polypeptide ligation. We summarize and discuss the designs and applications of binding growth factors prepared by such conjugation approaches. PMID:22754349

Tada, Seiichi; Kitajima, Takashi; Ito, Yoshihiro

2012-01-01

154

Synthetic heparin-binding growth factor analogs  

DOEpatents

The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

Pena, Louis A.; Zamora, Paul; Lin, Xinhua; Glass, John D.

2007-01-23

155

Experience gained during the long term cultivation of keratinocytes for treatment of burns patients.  

PubMed

Both allogenic and autologous cultured skin cells have been used clinically on burn patients. In vitro cultivation of human keratinocytes has been routinely provided by the Central Tissue Bank in Bratislava since 1996, with an average annual production of around 7,000 cm(2). Keratinocytes have been cultivated using a version of the original by Rheinwald and Green (Cell 6:317-330, 1975) methodology which has been modified over time in our laboratory as we gained more experience with this serial passage system. We have observed that the growth of cultured keratinocytes depends on several important factors, including the timing of skin sample procurement, the method of skin sample procurement, the general condition of the patient, the quality and composition of the culture media and, to a lesser extent, the age of the patient. We aim to share our experience with other cell cultivation facilities. PMID:21847560

Dragú?ová, Jana; Kabát, Peter; Koller, Ján; Jarabinská, Valéria

2012-08-01

156

RIP2: A novel player in the regulation of keratinocyte proliferation and cutaneous wound repair?  

SciTech Connect

We could recently demonstrate an important role of receptor interacting protein 4 (RIP4) in the regulation of keratinocyte differentiation. Now, we analyzed a potential role of the RIP4 homolog RIP2 in keratinocytes. Specifically, we demonstrate here that rip2 expression is induced by scratch-wounding and after the induction of differentiation in these cells. Furthermore, serum growth factors and cytokines can induce rip2, with TNF-{alpha}-dependent induction being dependent on p38 MAPK. In addition, we demonstrate that scratch-induced upregulation of rip2 expression is completely blocked by the steroid dexamethasone. Since we also show that RIP2 is an important player in the regulation of keratinocyte proliferation, these data suggest that inhibition of rip2 upregulation after wounding might contribute to the reduced and delayed wound re-epithelialization phenotype seen in glucocorticoid-treated patients.

Adams, Stephanie; Valchanova, Ralitsa S. [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany)] [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany); Munz, Barbara, E-mail: barbara.munz@charite.de [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany)] [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany)

2010-03-10

157

A Modeling Approach to Study the Effect of Cell Polarization on Keratinocyte Migration  

PubMed Central

The skin forms an efficient barrier against the environment, and rapid cutaneous wound healing after injury is therefore essential. Healing of the uppermost layer of the skin, the epidermis, involves collective migration of keratinocytes, which requires coordinated polarization of the cells. To study this process, we developed a model that allows analysis of live-cell images of migrating keratinocytes in culture based on a small number of parameters, including the radius of the cells, their mass and their polarization. This computational approach allowed the analysis of cell migration at the front of the wound and a reliable identification and quantification of the impaired polarization and migration of keratinocytes from mice lacking fibroblast growth factors 1 and 2 – an established model of impaired healing. Therefore, our modeling approach is suitable for large-scale analysis of migration phenotypes of cells with specific genetic defects or upon treatment with different pharmacological agents. PMID:25671585

Fuhr, Matthias Jörg; Meyer, Michael; Fehr, Eric; Ponzio, Gilles

2015-01-01

158

Growth factors, nutrient signaling, and cardiovascular aging  

PubMed Central

Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the great majority of the organisms studied. In particular, the enzymes activated by growth hormone (GH), insulin and insulin-like growth factor 1 (IGF-I) in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction (DR), which reduces the level of IGF-I and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases and deficiencies in GH signaling and IGF-I are strongly associated with protection from cancer and diabetes in both mice and humans, but their role in cardiac function and cardiovascular diseases is controversial. Here we review the link between growth factors, cardiac function and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans. PMID:22499903

Fontana, Luigi; Vinciguerra, Manlio; Longo, Valter D.

2012-01-01

159

Antithrombin Regulates Matriptase Activity Involved in Plasmin Generation, Syndecan Shedding, and HGF Activation in Keratinocytes  

PubMed Central

Matriptase, a membrane-associated serine protease, plays an essential role in epidermal barrier function through activation of the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin. The matriptase-prostasin proteolytic cascade is tightly regulated by hepatocyte growth factor activator inhibitor (HAI)-1 such that matriptase autoactivation and prostasin activation occur simultaneously and are followed immediately by the inhibition of both enzymes by HAI-1. However, the mechanisms whereby matriptase acts on extracellular substrates remain elusive. Here we report that some active matriptase can escape HAI-1 inhibition by being rapidly shed from the cell surface. In the pericellular environment, shed active matriptase is able to activate hepatocyte growth factor (HGF), accelerate plasminogen activation, and shed syndecan 1. The amount of active matriptase shed is inversely correlated with the amount of antithrombin (AT) bound to the surface of the keratinocytes. Binding of AT to the surface of keratinocytes is dependent on a functional heparin binding site, Lys-125, and that the N-glycosylation site Asn-135 be unglycosylated. This suggests that ?-AT, and not ?-AT, is responsible for regulation of pericellular matriptase activity in keratinocytes. Keratinocytes appear to rely on AT to regulate the level of pericellular active matriptase much more than breast and prostate epithelial cells in which AT regulation of matriptase activity occurs at much lower levels than keratinocytes. These results suggest that keratinocytes employ two distinct serine protease inhibitors to control the activation and processing of two different sets of matriptase substrates leading to different biological events: 1) HAI-1 for prostasin activation/inhibition, and 2) AT for the pericellular proteolysis involved in HGF activation, accelerating plasminogen activation, and shedding of syndecans. PMID:23675430

Chen, Ya-Wen; Xu, Zhenghong; Baksh, Adrienne N. H.; Wang, Jehng-Kang; Chen, Chiu-Yuan; Swanson, Richard; Olson, Steve T.; Kataoka, Hiroaki; Johnson, Michael D.; Lin, Chen-Yong

2013-01-01

160

Regulation of Growth Factor Receptors by Gangliosides  

NSDL National Science Digital Library

Growth factor receptors are important in controlling many cellular functions, such as growth, differentiation, and disease. Growth factor receptors activate numerous signal transduction pathways within cells; however, how one growth factor receptor orchestrates multiple signal transduction pathways is not clear. This review focuses on a ubiquitous component of the plasma membrane, called "gangliosides," and how they modulate growth factor receptors at the cell membrane. Gangliosides are complex structures that consist of two parts--a lipid ceramide moiety and a carbohydrate head structure. Studies over the past two decades have demonstrated that different gangliosides can enhance or inhibit growth factor receptor activity. However, ganglioside modulation of growth factor receptors is more complex than simply stimulation or inhibition. We present and discuss three models of how gangliosides regulate growth factor receptors: (i) modulation of ligand binding, (ii) regulation of receptor dimerization, and (iii) regulation of receptor activation state and subcellular distribution. On the basis of these models, we speculate about the physiological consequences of ganglioside regulation of growth factor receptors.

Erik A. Miljan (Chicago; Children's Memorial Medical Center REV)

2002-11-26

161

Roles for Growth Factors in Cancer Progression  

NSDL National Science Digital Library

Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy.

Esther Witsch (Weizmann Institute of Science)

2010-04-01

162

Staphylococcus aureus keratinocyte invasion is mediated by integrin-linked kinase and Rac1.  

PubMed

Staphylococcus aureus is a major component of the skin microbiota and causes a large number of serious infections. S. aureus first interacts with epidermal keratinocytes to breach the epidermal barrier through mechanisms not fully understood. By use of primary keratinocytes from mice with epidermis-restricted Ilk gene inactivation and control integrin-linked kinase (ILK)-expressing littermates, we investigated the role of ILK in epidermal S. aureus invasion. Heat-killed, but not live, bacteria were internalized to Rab5- and Rab7-positive phagosomes, and incubation with keratinocyte growth factor increased their uptake 2.5-fold. ILK-deficient mouse keratinocytes internalized bacteria 2- to 4-fold less efficiently than normal cells. The reduced invasion by live S. aureus of ILK-deficient cells was restored in the presence of exogenous, constitutively active Rac1. Thus, Rac1 functions downstream from ILK during invasion. Further, invasion by S. aureus of Rac1-deficient cells was 2.5-fold lower than in normal cells. Paradoxically, staphylococcal cutaneous penetration of mouse skin explants with ILK-deficient epidermis was 35-fold higher than that of normal skin, indicating defects in epidermal barrier function in the absence of ILK. Thus, we identified an ILK-Rac1 pathway essential for bacterial invasion of keratinocytes, and established ILK as a key contributor to prevent invasive staphylococcal cutaneous infection. PMID:25416549

Sayedyahossein, Samar; Xu, Stacey X; Rudkouskaya, Alena; McGavin, Martin J; McCormick, John K; Dagnino, Lina

2015-02-01

163

Persea americana Mill. Seed: Fractionation, Characterization, and Effects on Human Keratinocytes and Fibroblasts  

PubMed Central

Methanolic avocado (Persea americana Mill., Lauraceae) seed extracts were separated by preparative HSCCC. Partition and HSCCC fractions were principally characterized by LC-ESI-MS/MS analysis. Their in vitro influence was investigated on proliferation, differentiation, cell viability, and gene expression on HaCaT and normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF). The methanol-water partition (M) from avocado seeds and HSCCC fraction 3 (M.3) were mostly composed of chlorogenic acid and its isomers. Both reduced NHDF but enhanced HaCaT keratinocytes proliferation. HSCCC fraction M.2 composed of quinic acid among chlorogenic acid and its isomers inhibited proliferation and directly induced differentiation of keratinocytes as observed on gene and protein level. Furthermore, M.2 increased NHDF proliferation via upregulation of growth factor receptors. Salidrosides and ABA derivatives present in HSCCC fraction M.6 increased NHDF and keratinocyte proliferation that resulted in differentiation. The residual solvent fraction M.7 contained among low concentrations of ABA derivatives high amounts of proanthocyanidins B1 and B2 as well as an A-type trimer and stimulated proliferation of normal cells and inhibited the proliferation of immortalized HaCaT keratinocytes. PMID:24371457

Ramos-Jerz, Maria del R.; Villanueva, Socorro; Jerz, Gerold; Winterhalter, Peter; Deters, Alexandra M.

2013-01-01

164

Persea americana Mill. Seed: Fractionation, Characterization, and Effects on Human Keratinocytes and Fibroblasts.  

PubMed

Methanolic avocado (Persea americana Mill., Lauraceae) seed extracts were separated by preparative HSCCC. Partition and HSCCC fractions were principally characterized by LC-ESI-MS/MS analysis. Their in vitro influence was investigated on proliferation, differentiation, cell viability, and gene expression on HaCaT and normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF). The methanol-water partition (M) from avocado seeds and HSCCC fraction 3 (M.3) were mostly composed of chlorogenic acid and its isomers. Both reduced NHDF but enhanced HaCaT keratinocytes proliferation. HSCCC fraction M.2 composed of quinic acid among chlorogenic acid and its isomers inhibited proliferation and directly induced differentiation of keratinocytes as observed on gene and protein level. Furthermore, M.2 increased NHDF proliferation via upregulation of growth factor receptors. Salidrosides and ABA derivatives present in HSCCC fraction M.6 increased NHDF and keratinocyte proliferation that resulted in differentiation. The residual solvent fraction M.7 contained among low concentrations of ABA derivatives high amounts of proanthocyanidins B1 and B2 as well as an A-type trimer and stimulated proliferation of normal cells and inhibited the proliferation of immortalized HaCaT keratinocytes. PMID:24371457

Ramos-Jerz, Maria Del R; Villanueva, Socorro; Jerz, Gerold; Winterhalter, Peter; Deters, Alexandra M

2013-01-01

165

Bone growth factors in maxillofacial skeletal reconstruction  

Microsoft Academic Search

Abstract.A literature review was performed to survey the available information on the potential of bone growth factors in skeletal reconstruction in the maxillofacial area. The aim of this review was to characterize the biological and developmental nature of the growth factors considered, their molecular level of activity and their osteogenic potential in craniofacial bone repair and reconstruction. A total of

H. Schliephake

2002-01-01

166

Double-Stranded RNA-Exposed Human Keratinocytes Promote Th1 Responses by Inducing a Type1 Polarized Phenotype in Dendritic Cells: Role of Keratinocyte-Derived Tumor Necrosis Factor ?, Type I Interferons, and Interleukin18  

Microsoft Academic Search

Dendritic cells play a key role in establishing the class of immune response against invading pathogens. Upon engagement with double-stranded RNA, a major bioactive constituent of many virus types, immature dendritic cells develop into type 1 immunostimulatory dendritic cells that promote Th1 responses. Immature dendritic cells reside in the epithelia and are in close contact with keratinocytes. We studied to

M Cristina Lebre; Jeanine C Antons; Pawel Kalinski; Joost H N Schuitemaker; Toni M M van Capel; Martien L Kapsenberg; Esther C de Jong

2003-01-01

167

Growth factor involvement in tension-induced skeletal muscle growth  

NASA Technical Reports Server (NTRS)

Long-term manned space travel will require a better understanding of skeletal muscle atrophy which results from microgravity. Astronaut strength and dexterity must be maintained for normal mission operations and for emergency situations. Although exercise in space slows the rate of muscle loss, it does not prevent it. A biochemical understanding of how gravity/tension/exercise help to maintain muscle size by altering protein synthesis and/or degradation rate should ultimately allow pharmacological intervention to prevent muscle atrophy in microgravity. The overall objective is to examine some of the basic biochemical processes involved in tension-induced muscle growth. With an experimental in vitro system, the role of exogenous and endogenous muscle growth factors in mechanically stimulated muscle growth are examined. Differentiated avian skeletal myofibers can be 'exercised' in tissue culture using a newly developed dynamic mechanical cell stimulator device which simulates different muscle activity patterns. Patterns of mechanical activity which significantly affect muscle growth and metabolic characteristics were found. Both exogenous and endogenous growth factors are essential for tension-induced muscle growth. Exogenous growth factors found in serum, such as insulin, insulin-like growth factors, and steroids, are important regulators of muscle protein turnover rates and mechanically-induced muscle growth. Endogenous growth factors are synthesized and released into the culture medium when muscle cells are mechanically stimulated. At least one family of mechanically induced endogenous factors, the prostaglandins, help to regulate the rates of protein turnover in muscle cells. Endogenously synthesized IGF-1 is another. The interaction of muscle mechanical activity and these growth factors in the regulation of muscle protein turnover rates with our in vitro model system is studied.

Vandenburgh, Herman H.

1993-01-01

168

Transforming growth factor ? and epidermal growth factor expression in experimental murine polycystic kidney disease  

Microsoft Academic Search

Cystic change in polycystic kidney disease (PKD) is associated with epithelial hyperplasia, altered fluid and electrolyte transport, and de-differentiation of renal tubular epithelium. The role of polypeptide growth factors as potential modulators of cystic change remains an area of controversy. In this study, the expression of epidermal growth factor (EGF) and transforming growth factor-a (TGFa) were assessed by immunohistochemistry and

Malcolm R. Ogborn; Sanjay Sareen

1996-01-01

169

Regulation of Early Embryonic Development by Growth Factors: Growth Factor Gene Expression in Cloned Bovine Embryos  

Microsoft Academic Search

A number of growth factor ligand and receptor genes are expressed by early embryos of the mouse, rat, cow, and sheep. Several growth factors have stimulatory effects on early embryos when added exogenously to the medium for culture of preimplanta- tion mammalian embryos. Growth factor supplemen- tation of simple defined medium for culture of early bovine embryos leads to a

Gilbert A. Schultz; Mark B. Harvey; Andrew J. Watson; Mayi Y. Arcellana-Panlilio; Karen Jones; Mark E. Westhusint

2010-01-01

170

THE EFFECT OF FIBROBLAST GROWTH FACTOR ON PC12 CELLS  

Microsoft Academic Search

PC12 cells, which differentiate morphologically and biochemically into sympathetic neuron-like cells when treated with nerve growth factor, also respond to fibroblast growth factor. Some of the changes induced by fibroblast growth factor are similar to those seen after nerve growth factor treatment. Specifically, pituitary fibroblast growth factor causes the formation of processes initially comparable to those produced by nerve growth

AKIFUMI TOGARI; GENEVA DICKENS; HIROSHI KUZUYA; GORDON GUROFF

1985-01-01

171

Growth factors from genes to clinical application  

SciTech Connect

The last decade has witnessed an explosion in the identification of growth factors and their receptors. This has been greatly facilitated by recombinant DNA technology, which has provided the tools not only to identify these proteins at the gene level but also to produce recombinant proteins for evaluating their biological activities. With the help of such techniques, we are moving toward an understanding of the biosynthesis of growth factors and their receptors, structure-function relationships, as well as mechanisms for intracellular signal transmission. The possibility of modifying these factors has opened new fields of clinical application. In this paper, four major areas of growth factor research are presented: the characterization of growth factor genes and their protein products, growth factor receptors and signal transduction by the receptors to mediate biological action, the biological actions of the various growth factors, and the role of growth factors in health and disease and their possible clinical application. Some of the topics covered include: structure of the IGFs and their variants; isoforms of PDGF receptor types; tyrosine kinase activation; structure of G-proteins in biological membranes; possible therapeutic application of NGF in the treatment of Parkinson's and Alzheimer's diseases; PDGF's possible role in the development of several fibroproliferative diseases and its therapeutic application in wound healing; and the possible use of angiogenic inhibitors in tumor treatment.

Sara, V.R. (Dept. of Pathology, Karolinska Hospital, Stockholm (SE)); Hall, K.; Low, H. (Dept. of Endocrinology, Karolinska Hospital, Stockholm (SE))

1990-01-01

172

Neuronal growth factors, neurotrophins and memory deficiency  

Microsoft Academic Search

CNS and PNS ontogenesis are regulated by various proteic factors, and the best characterized of which still remains Nerve Growth Factor (NGF), a molecule exerting trophic, tropic (i.e. directing growing axons toward NGF-releasing target tissue) and differentiative effects on a number of neural and non-neural (e.g. mast-cells) cell lines. Other Growth Factors (GFs), called ‘neurotrophins’ (BDNF, NT-3, NT-4, NT-5) also

Gemma Calamandrei; Enrico Alleva

1995-01-01

173

Induction of PDGF-B in TCA-treated epidermal keratinocytes.  

PubMed

Trichloroacetic acid (TCA) is one of the most widely used peeling agents, and induces full necrosis of the whole epidermis, followed by reconstitution of the epidermis and the matrix of the papillary dermis. The cytotoxic effects of TCA, such as suppressing proliferation of keratinocytes and fibroblasts and protein synthesis by fibroblasts, have already been reported. However, the entire biological mechanism responsible for TCA peeling has yet to be determined. Hypothetical activation effects of TCA treatment on epidermal cells to induce production of growth factors and cytokines are examined, and are compared with its cytotoxic effects in terms of time course and applied TCA concentrations. After various periods of incubation with TCA, viability of Pam212 murine keratinocytes was investigated with MTT assay and dye exclusion assay, and production of growth factors and cytokines with reverse transcription-polymerase chain reaction (RT-PCR). Changes in platelet-derived growth factor (PDGF)-B mRNA expression and protein production in the human skin specimens after TCA application were then examined by RT-PCR and immunohistochemistry, respectively. Incubation with TCA showed cytotoxicity and induced death of Pam212 cells, depending on the incubation period and the TCA concentration. In addition, expressions of PDGF-B, tumor growth factor (TGF)-alpha, TGF- beta1 and vascular endothelial growth factor, which are the growth factors reportedly secreted from keratinocytes during wound healing, were all detected in Pam212 cells after short-term treatment with TCA. Expressions of inflammatory cytokines such as interleukin (IL)-1 and IL-10 were also induced. In TCA-treated NIH-3T3 fibroblasts, in contrast, observed was upregulation of only keratinocyte growth factor, which is reportedly secreted from fibroblasts, as well as the similar cytotoxic effect. In human skin, PDGF-B mRNA expression became significantly upregulated after TCA application, and then immediately downregulated. Immunoreactive PDGF-B in the cytoplasm of keratinocytes became detectable throughout the epidermis after TCA application, reached maximum after the peak of mRNA expression, and then declined significantly over 24 h when the epidermis became completely necrotic. The TCA-treated epidermis acts as a major source of growth factors, including PDGF-B, before undergoing full necrosis. This effect might contribute to a promotion of re-epithelialization and dermal regeneration without wound contraction and scarring. PMID:17724602

Yonei, Nozomi; Kanazawa, Nobuo; Ohtani, Toshio; Furukawa, Fukumi; Yamamoto, Yuki

2007-11-01

174

Proliferation and motility of HaCaT keratinocyte derivatives is enhanced by fibroblast nemosis  

SciTech Connect

The role of paracrine tumor-stroma regulation in the progression of cancer is under intense investigation. Activated fibroblasts are key components of the tumor microenvironment providing the soluble factors mediating the regulation. Nemosis is an experimental model to study these parameters: formation of a multicellular spheroid activates fibroblasts and leads to increased production of soluble factors involved in the promotion of growth and motility. Role of nemosis was investigated in the tumorigenesis of HaCaT derivatives representing skin carcinoma progression. Conditioned medium from fibroblast spheroids increased proliferation rate of HaCaT derivatives. Expression of proliferation marker Ki-67 increased significantly in benign A5 and low-grade malignant II-4 cells, but did not further increase in the metastatic RT3 cells. Expression of p63, keratinocyte stem cell marker linked to cancer progression, was augmented by medium from nemotic fibroblasts; this increase was also seen in RT3 cells. Scratch-wound healing of the keratinocytes was enhanced in response to fibroblast nemosis. Neutralizing antibodies against growth factors inhibited wound healing to some extent; the response varied between benign and malignant keratinocytes. Migration and invasion were enhanced by conditioned medium from nemotic fibroblasts in benign and low-grade malignant cells. RT3 keratinocyte migration was further augmented, but invasion was not, indicating their intrinsic capacity to invade. Our data demonstrate that fibroblast nemosis increases proliferation and motility of HaCaT keratinocyte derivatives, and thus nemosis can be used as a model to study the role of soluble factors secreted by fibroblasts in tumor progression.

Raesaenen, Kati, E-mail: kati.rasanen@helsinki.fi [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)] [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland); Vaheri, Antti, E-mail: antti.vaheri@helsinki.fi [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)] [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)

2010-06-10

175

Activated keratinocytes in the epidermis of hypertrophic scars.  

PubMed

The etiology of hypertrophic scarring, a pathological end point of wound healing, is unknown. The scars most commonly occur when epithelialization has been delayed during, for example, the healing of deep dermal burn wounds. Hypertrophic scars are conventionally described as a dermal pathology in which the epidermis has only a passive role. In this study, the expression of keratin intermediate filament proteins and filaggrin has been investigated in the epidermis of hypertrophic scars and site-matched controls from the same patients. Hypertrophic scar epidermis was found to express the hyperproliferative keratins K6 and K16 in interfollicular epidermis in association with K17 and precocious expression of filaggrin. K16 mRNA was localized by in situ hybridization using a highly specific cRNA probe. In contrast to the immunohistochemical location of K16 protein, the K16 mRNA was found to be expressed in the basal cell layer of normal skin. In hypertrophic scars the mRNA distribution corroborated the abnormal K16 protein distribution. These results suggest the keratinocytes in hypertrophic scar epidermis have entered an alternative differentiation pathway and are expressing an activated phenotype. Activated keratinocytes are a feature of the early stages of wound healing producing growth factors that influence fibroblasts, endothelial cells, and the inflammatory response. We propose that cellular mechanisms in the pathogenesis of hypertrophic scarring are more complex than isolated dermal phenomena. The persistence of activated keratinocytes in hypertrophic scar epidermis implicates abnormal epidermal-mesenchymal interactions. PMID:9588880

Machesney, M; Tidman, N; Waseem, A; Kirby, L; Leigh, I

1998-05-01

176

Hepatoma-derived growth factor and its role in keloid pathogenesis  

PubMed Central

Abstract Hepatoma-derived growth factor (HDGF) is a novel mitogenic growth factor that has been implicated in many different carcinomas. Its role in keloid biology has not yet been investigated. The present study is aimed at examining the role of HDGF in keloid pathogenesis. Immunohistochemical staining and Western blot analyses were used to examine in vivo localization and expression of HDGF in keloid and normal skin tissue. This was followed by the detection of HDGF expression in fibroblasts cultured in vitro and fibroblasts exposed to serum. To investigate the effect of epithelial–mesenchymal interactions, a two-chamber system was employed in which keratinocytes on membrane inserts were co-cultured with the fibroblasts. HDGF expression levels in all cell extracts and conditioned media were assayed through Western blot analysis. In another set of experiments, the effect of exogenous recombinant HDGF on keloid fibroblasts (KF) and normal fibroblasts (NF) was examined. Cell proliferation was assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and by quantifying proliferating cell nuclear antigen (PCNA) expression. Downstream targets of HDGF were identified by detecting their expression through Western blot analysis. Our results indicate that there was an increase in HDGF expression in the dermis of keloid compared with normal skin tissue. The application of serum and epithelial–mesenchymal interactions did not seem to have any effect on intracellular HDGF expression levels. However, co-culturing keloid keratinocytes with KFs resulted in increased HDGF secretion when compared with monoculture or normal controls. Furthermore, treatment with exogenous recombinant HDGF was found to increase the proliferation of KFs, activate the extracellular signal-regulated kinase (ERK) pathway and up-regulate the secretion of vascular endothelial growth factor (VEGF). PMID:19432814

Ooi, BNS; Mukhopadhyay, A; Masilamani, J; Do, DV; Lim, CP; Cao, XM; Lim, IJ; Mao, L; Ren, HN; Nakamura, H; Phan, TT

2010-01-01

177

Growth factors, tumor promoters, and cancer genes  

SciTech Connect

This book contains over 30 selections. Some of the titles are: Growth-regulated genes and human leukemias; Tyrosyl and phosphatidylinositol kinases of human erythrocyte membranes; Growth factors, oncogenes, and multistage carcinogenesis; Tumorigenic transformation of human teratocarcinoma cells by activated ras oncogene but not the homologous photo-oncogene; and Genes that cooperate with tumor promoters in transformation.

Colburn, N.H.; Moses, H.L.; Stanbridge, E.J.

1988-01-01

178

Release of growth factors after arthroscopic acromioplasty  

Microsoft Academic Search

It has recently been postulated that a variety of growth factors may be released from cancellous bone after an acromioplasty.\\u000a The aim of this study was to demonstrate the presence of growth factors in the subacromial space after acromioplasty. Between\\u000a October 2006 and March 2007, 23 patients underwent arthroscopic acromioplasty. A sample of at least 3 ml of fluid from the

Pietro Randelli; Fabrizio Margheritini; Paolo Cabitza; Giada Dogliotti; Massimiliano M. Corsi

2009-01-01

179

Vascular Endothelial Growth Factors (VEGFs) and Stroke  

PubMed Central

Vascular endothelial growth factors (VEGFs) have been shown to participate in atherosclerosis, arteriogenesis, cerebral edema, neuroprotection, neurogenesis, angiogenesis, postischemic brain and vessel repair, and the effects of transplanted stem cells in experimental stroke. Most of these actions involve VEGF-A and the VEGFR-2 receptor, but VEGF-B, placental growth factor, and VEGFR-1 have been implicated in some cases as well. VEGF signaling pathways represent important potential targets for the acute and chronic treatment of stroke. PMID:23475070

Greenberg, David A.; Jin, Kunlin

2013-01-01

180

A Keratinocyte’s Course of Life  

Microsoft Academic Search

An adequate permeability barrier function of the mammalian epidermis is guaranteed by the characteristic architecture of the stratum corneum. This uppermost layer consists of a highly organized extracellular lipid compartment which is tightly joined to the corneocytes. The generation of the extracellular lipid compartment and the transformation of the keratinocytes into corneocytes are the main features of epidermal differentiation. However,

E. Houben; K. De Paepe; V. Rogiers

2007-01-01

181

The Role of Fibroblast Growth Factors in Tumor Growth  

PubMed Central

Biological processes that drive cell growth are exciting targets for cancer therapy. The fibroblast growth factor (FGF) signaling network plays a ubiquitous role in normal cell growth, survival, differentiation, and angiogenesis, but has also been implicated in tumor development. Elucidation of the roles and relationships within the diverse FGF family and of their links to tumor growth and progression will be critical in designing new drug therapies to target FGF receptor (FGFR) pathways. Recent studies have shown that FGF can act synergistically with vascular endothelial growth factor (VEGF) to amplify tumor angiogenesis, highlighting that targeting of both the FGF and VEGF pathways may be more efficient in suppressing tumor growth and angiogenesis than targeting either factor alone. In addition, through inducing tumor cell survival, FGF has the potential to overcome chemotherapy resistance highlighting that chemotherapy may be more effective when used in combination with FGF inhibitor therapy. Furthermore, FGFRs have variable activity in promoting angiogenesis, with the FGFR-1 subgroup being associated with tumor progression and the FGFR-2 subgroup being associated with either early tumor development or decreased tumor progression. This review highlights the growing knowledge of FGFs in tumor cell growth and survival, including an overview of FGF intracellular signaling pathways, the role of FGFs in angiogenesis, patterns of FGF and FGFR expression in various tumor types, and the role of FGFs in tumor progression. PMID:19508171

Korc, Murray; Friesel, Robert E.

2013-01-01

182

Predictive factors for intrauterine growth restriction.  

PubMed

Reduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies. PMID:25408721

Albu, A R; Anca, A F; Horhoianu, V V; Horhoianu, I A

2014-06-15

183

Signaling mechanism underlying the promotion of keratinocyte migration by angiotensin II.  

PubMed

Re-epithelialization begins early during skin wound healing and is regulated by various growth factors and cytokines. Angiotensin II promotes the migration of keratinocytes and thereby contributes to wound healing. We investigated the mechanism by which angiotensin II stimulates human keratinocyte migration. Angiotensin II-induced keratinocyte migration was inhibited by an angiotensin II type 1 receptor (AT1R) antagonist (candesartan) or an angiotensin II type 2 receptor (AT2R) antagonist (PD123319) as well as by depletion of AT1R or AT2R. A biased agonist for AT1R, [Sar(1),Ile(4),Ile(8)]angiotensin II, induced cell migration, whereas depletion of ?-arrestin2 inhibited angiotensin II-induced migration. Angiotensin II-induced migration was blocked by neutralizing antibodies to transforming growth factor-? (TGF-?) as well as by the TGF-? receptor inhibitor SB431542. The amount of TGF-?1 was increased in the culture medium of angiotensin II-treated cells, and this effect was inhibited by candesartan or PD123319. Both angiotensin II- and TGF-?-induced cell migration were inhibited by neutralizing antibodies to the epidermal growth factor (EGF) receptor but not by those to EGF receptor ligands. Angiotensin II-induced phosphorylation of the EGF receptor, and this effect was inhibited by candesartan, PD123319, SB431542, or depletion of ?-arrestin2, but not by neutralizing antibodies to heparin-binding EGF-like growth factor. Our results indicate that ?-arrestin-dependent signaling downstream of AT1R as well as AT2R signaling are necessary for angiotensin II-induced keratinocyte migration, and that such signaling promotes generation of the active form of TGF-?, consequent activation of the TGF-? receptor, and transactivation of the EGF receptor by the TGF-? receptor. PMID:25473119

Sakai, Hiroki; Matsuura, Kenji; Tanaka, Yoshie; Honda, Takeshi; Nishida, Teruo; Inui, Makoto

2015-02-01

184

Predictive factors for intrauterine growth restriction  

PubMed Central

Abstract Reduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies. Abbreviations: SGA = small for gestational age; IUGR = intrauterine growth restriction; FGR = fetal growth restriction; IUFD = intrauterine fetal demise; HIV = human immunodeficiency virus; PAPP-A = pregnancy associated plasmatic protein A; ?-hCG = beta human chorionic gonadotropin; MoM = multiple of median; ADAM-12 = A-disintegrin and metalloprotease 12; PP-13 = placental protein 13; VEGF = vascular endothelial growth factor; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UAD = uterine arteries Doppler ultrasound; RI = resistence index; PI = pulsatility index; VOCAL = Virtual Organ Computer–Aided Analysis software; VI = vascularization index; FI = flow index; VFI = vascularization flow index; PQ = placental quotient PMID:25408721

Albu, AR; Anca, AF; Horhoianu, VV; Horhoianu, IA

2014-01-01

185

Kinin B2 receptor-coupled signal transduction in human cultured keratinocytes.  

PubMed

Kinins are key pro-inflammatory peptides that exhibit mitogenic effects in tissue-specific cellular systems. Since the life span of the keratinocyte is regulated by receptors that control proliferation and differentiation, and since both processes are affected during wound healing, we have examined the consequence of kinin B2 receptors (B2R) activation in cultured human keratinocytes. Stimulation of keratinocytes by Lys-bradykinin (LBK) induced a rapid and sustained phosphorylation of 42/44 mitogen-activated protein kinase (MAPK) that translocated to the nucleus, and decreased only after 120 min of stimulation. Kinin B1 and B2 receptor (B1R and B2R) antagonists showed that phosphorylation was mainly because of B2R activation. The GF109203X inhibitor almost completely abolished the effect of LBK, suggesting the involvement of protein kinase C in the signal cascade. MAPK phosphorylation was partially dependent on epidermal growth factor receptor transactivation as assessed by the selective inhibitor, AG1478. LBK stimulation did not result in cell proliferation, but produced a rapid c-Fos expression, nuclear translocation of nuclear factor-kappaB, and a moderated (pro)filaggrin synthesis, indicating that it may modulate cell differentiation. Our results support the view that kinins may affect the life span of human keratinocytes and highlight the importance that kinin peptides may have in the pathogenesis and/or progression of skin diseases. PMID:15654972

Vidal, Maria A; Astroza, Angel; Matus, Carola E; Ehrenfeld, Pamela; Pavicic, Francisca; Sanchez, Tamara; Salem, Christian; Figueroa, Jaime; Concha, Miguel; Gonzalez, Carlos B; Figueroa, Carlos D

2005-01-01

186

Nerve growth factor: from neurotrophin to neurokine  

Microsoft Academic Search

Nerve growth factor (NGF) is largely known as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurones and basal forebrain cholinergic nuclei during development and maturation. However, NGF also exerts a modulatory role on sensory, nociceptive nerve physiology during adulthood that appears to correlate with hyperalgesic phenomena occurring in tissue inflammation.

Rita Levi-Montalcini; Stephen D. Skaper; Roberto Dal Toso; Lucia Petrelli; Alberta Leon

1996-01-01

187

Calcium-Regulated Differentiation of Normal Human Epidermal Keratinocytes in Chemically Defined Clonal Culture and Serum-Free Serial Culture  

Microsoft Academic Search

An improved serum-free culture system has been developed for normal human epidermal keratinocytes (HK), Short-term clonal growth and differentiation studies are routinely performed in a defined medium consisting of optimized nutrient medium MCDB 153 supplemented with epidermal growth factor, insulin, hydrocortisone, ethanolamine, and phosphoethanolamine. A small amount of whole bovine pituitary extract (wBPE) is added for initiation of primary cultures,

Steven T. Boyce; Richard G. Ham

1983-01-01

188

Placenta Growth Factor in Diabetic Wound Healing  

PubMed Central

Reduced microcirculation and diminished expression of growth factors contribute to wound healing impairment in diabetes. Placenta growth factor (PlGF), an angiogenic mediator promoting pathophysiological neovascularization, is expressed during cutaneous wound healing and improves wound closure by enhancing angiogenesis. By using streptozotocin-induced diabetic mice, we here demonstrate that PlGF induction is strongly reduced in diabetic wounds. Diabetic transgenic mice overexpressing PlGF in the skin displayed accelerated wound closure compared with diabetic wild-type littermates. Moreover, diabetic wound treatment with an adenovirus vector expressing the human PlGF gene (AdCMV.PlGF) significantly accelerated the healing process compared with wounds treated with a control vector. The analysis of treated wounds showed that PlGF gene transfer improved granulation tissue formation, maturation, and vascularization, as well as monocytes/macrophages local recruitment. Platelet-derived growth factor, fibroblast growth factor-2, and vascular endothelial growth factor mRNA levels were increased in AdCMV.PlGF-treated wounds, possibly enhancing PlGF-mediated effects. Finally, PlGF treatment stimulated cultured dermal fibroblast migration, pointing to a direct role of PlGF in accelerating granulation tissue maturation. In conclusion, our data indicate that reduced PlGF expression contributes to impaired wound healing in diabetes and that PlGF gene transfer to diabetic wounds exerts therapeutic activity by promoting different aspects of the repair process. PMID:17003476

Cianfarani, Francesca; Zambruno, Giovanna; Brogelli, Laura; Sera, Francesco; Lacal, Pedro Miguel; Pesce, Maurizio; Capogrossi, Maurizio C.; Failla, Cristina Maria; Napolitano, Monica; Odorisio, Teresa

2006-01-01

189

Transforming growth factor-? regulates production of proteoglycans by mesangial cells  

Microsoft Academic Search

Transforming growth factor-? regulates production of proteoglycans by mesangial cells. Accumulation of glomerular extracellular matrix is a prominent feature of most forms of progressive glomerular disease. Since some growth factors may play a role in extracellular matrix production, we examined the effects of transforming growth factor-? (TGF-?), interleukin 1, platelet derived growth factor, and tumor necrosis factor on the production

Wayne A Border; Seiya Okuda; Lucia R Languino; Erkki Ruoslahti

1990-01-01

190

Virus transcript levels and cell growth rates after naturally occurring HPV16 integration events in basal cervical keratinocytes  

PubMed Central

Cervical carcinogenesis is characterized by a clonal selection process in which the high-risk human papillomavirus (HRHPV) genome usually changes from the extra-chromosomal (episomal) state seen in productive infections to DNA that is integrated into host chromosomes. However, it is not clear whether all HRHPV integration events provide cells with a selective growth advantage compared with the episome-containing cells from which they originate. It is also unclear whether selection of cells containing a particular integrant from a mixed population simply reflects the highest levels of virus oncogene expression or has additional determinants. These early events in cervical carcinogenesis cannot readily be addressed by cross-sectional studies of clinical samples. We used the W12 model system to generate a panel of cervical squamous cell clones that were derived from an identical background under non-competitive conditions and differed only by the genomic site of HPV16 integration. Compared with the ‘baseline’ episome-containing cells from which they were isolated, only 9/17 clones (53%) showed significantly greater growth rates and only 7/17 (41%) showed significantly greater expression of the major virus oncogenes E7/E6. There were significant variations in levels of HPV16 transcription per DNA template, changes that were associated with histone modifications in the integrated virus chromatin. Cell growth rates showed only weak and non-significant associations with protein and mRNA levels for E7, E6, and the mean E7/E6 values. We conclude that HPV16 integration in basal cervical cells does not necessarily lead to increased levels of virus oncogenes, or to a competitive growth advantage, when compared with the initiating episome-containing cells. PMID:24752734

Scarpini, Cinzia G; Groves, Ian J; Pett, Mark R; Ward, Dawn; Coleman, Nicholas

2014-01-01

191

Overexpression of phospholipase C? in keratinocytes upregulates cytokine expression and causes dermatitis with acanthosis and T-cell infiltration.  

PubMed

Phospholipase C? (PLC?) is an effector of Ras and Rap small GTPases. We showed previously using PLC?-deficient mice that PLC? plays a critical role in activation of cytokine production in non-immune skin cells in a variety of inflammatory reactions. For further investigation of its role in inflammation, we created transgenic mice overexpressing PLC? in epidermal keratinocytes. The resulting transgenic mice spontaneously developed skin inflammation as characterized by formation of adherent silvery scales, excessive growth of keratinocytes, and aberrant infiltration of immune cells such as T cells and DC. Development of the skin symptoms correlated well with increased expression of factors implicated in human inflammatory skin diseases, such as IL-23, in keratinocytes, and with the accumulation of CD4(+) T cells producing IL-22, a potent inducer of keratinocyte proliferation. Intradermal injection of a blocking antibody against IL-23 as well as treatment with the immunosuppressant FK506 reversed these skin phenotypes, which was accompanied by suppression of the IL-22-producing T-cell infiltration. These results reveal a crucial role of PLC? in the development of skin inflammation and suggest a mechanism in which PLC? induces the production of cytokines including IL-23 from keratinocytes, leading to the activation of IL-22-producing T cells. PMID:21182091

Takenaka, Nobuyuki; Edamatsu, Hironori; Suzuki, Noboru; Saito, Hiromitsu; Inoue, Yukiko; Oka, Masahiro; Hu, Lizhi; Kataoka, Tohru

2011-01-01

192

Hyaluronan metabolism in human keratinocytes and atopic dermatitis skin is driven by a balance of hyaluronan synthases 1 and 3.  

PubMed

Hyaluronan (HA) is a glycosaminoglycan synthesized directly into the extracellular matrix by three hyaluronan synthases (HAS1, HAS2, and HAS3). HA is abundantly synthesized by keratinocytes but its epidermal functions remain unclear. We used culture models to grow human keratinocytes as autocrine monolayers or as reconstructed human epidermis (RHE) to assess HA synthesis and HAS expression levels during the course of keratinocyte differentiation. In both the models, epidermal differentiation downregulates HAS3 mRNA expression while increasing HAS1 without significant changes in hyaluronidase expression. HA production correlates with HAS1 mRNA expression level during normal differentiation. To investigate the regulation of HAS gene expression during inflammatory conditions linked to perturbed differentiation, lesional and non-lesional skin biopsies of atopic dermatitis (AD) patients were analyzed. HAS3 mRNA expression level increases in AD lesions compared with healthy and non-lesional skin. Simultaneously, HAS1 expression decreases. Heparin-binding EGF-like growth factor (HB-EGF) is upregulated in AD epidermis. An AD-like HAS expression pattern is observed in RHE incubated with HB-EGF. These results indicate that HAS1 is the main enzyme responsible for HA production by normal keratinocytes and thus, must be considered as an actor of normal keratinocyte differentiation. In contrast, HAS3 can be induced by HB-EGF and seems mainly involved in AD epidermis. PMID:24658508

Malaisse, Jérémy; Bourguignon, Virginie; De Vuyst, Evelyne; Lambert de Rouvroit, Catherine; Nikkels, Arjen F; Flamion, Bruno; Poumay, Yves

2014-08-01

193

Comparative effects of polyphenols from green tea (EGCG) and soybean (genistein) on VEGF and IL8 release from normal human keratinocytes stimulated with the proinflammatory cytokine TNFa  

Microsoft Academic Search

In skin inflammation, vascular endothelial growth factor (VEGF) and IL-8 play an important role and are produced by activated keratinocytes. Recently, some polyphenols have been reported to exhibit antiinflammatory and antiangiogenic properties. We therefore evaluated the effects of green tea, its major component epigallocatechin-3-gallate (EGCG) and an isoflavone derived from soybean (genistein) on the release of VEGF and IL-8 by

Sandra Trompezinski; Alain Denis; Daniel Schmitt; Jacqueline Viac

2003-01-01

194

A Novel Role of the NRF2 Transcription Factor in the Regulation of Arsenite-Mediated Keratin 16 Gene Expression in Human Keratinocytes  

PubMed Central

Background Inorganic sodium arsenite (iAs) is a ubiquitous environmental contaminant and is associated with an increased risk of skin hyperkeratosis and cancer. Objectives We investigated the molecular mechanisms underlying the regulation of the keratin 16 (K16) gene by iAs in the human keratinocyte cell line HaCaT. Methods We performed reverse transcriptase polymerase chain reaction, luciferase assays, Western blots, and electrophoretic mobility shift assays to determine the transcriptional regulation of the K16 gene by iAs. We used gene overexpression approaches to elucidate the nuclear factor erythroid-derived 2 related factor 2 (NRF2) involved in the K16 induction. Results iAs induced the mRNA and protein expression of K16. We also found that the expression of K16 was transcriptionally induced by iAs through activator protein-1–like sites and an antioxidant response element (ARE) in its gene promoter region. Treatment with iAs also enhanced the production and translocation of the NRF2 transcription factor, an ARE-binding protein, into the nucleus without modification of its mRNA expression. In addition, iAs elongated the half-life of the NRF2 protein. When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. Conclusions Our data clearly indicate that the K16 gene is a novel target of NRF2. Furthermore, our findings also suggest that NRF2 has opposing roles in the cell—in the activation of detoxification pathways and in promoting the development of skin disorders. PMID:18629308

Endo, Hitoshi; Sugioka, Yoshihiko; Nakagi, Yoshihiko; Saijo, Yasuaki; Yoshida, Takahiko

2008-01-01

195

Peptide growth factors: clinical and therapeutic strategies.  

PubMed

The literature contains many accounts of studies in which tumour growth has been accelerated by administration of a particular mitogen and the response then inhibited by co-administration of the corresponding antagonist. Much effort has been focused on the development of cytokine or growth factor antagonists. Like most other cancer therapies, biological therapies will undoubtedly have undesirable toxicities because the proteins they target may not be unique to malignant cells. We reviewed the clinical and therapeutic potential of growth factor agonists and antagonists in some non urologic and urologic diseases. In a recent report we demonstrated that both androgen and antiandrogen treatments enhance the proliferation rate of the hormone-dependent prostate cancer cell line LNCaP, expressing a mutated androgen receptor. Simultaneous treatment with 1 nM R1881 and 100 nM OH-Flutamide, completely counteracted the androgen-induced increase of Epidermal Growth Factor (EGF) levels. Moreover we found that Testosterone, DHT and EGF are mainly concentrated in the periurethral zone in human BPH and long term treatment with Finasteride and with Flutamide modify the distribution and concentration of these factors. Some authors analyzed whether and addition of aurin tricarboxylic acid (ATA) can reduce the growth rate of basic FGF-dependent cells in a manner similar to suramin. PMID:9228827

Di Silverio, F; Sciarra, A; Di Nicola, S; Di Chiro, C

1997-06-01

196

Combined treatment with sodium butyrate and PD153035 enhances keratinocyte differentiation  

PubMed Central

Epidermal growth factor (EGF) receptor (EGFR) signaling is a critical determinant of keratinocyte proliferation and differentiation in both normal and diseased skin. Here we explore the effects of combined treatment with the differentiation-promoting agent sodium butyrate (SB) and the EGFR inhibitor (EGFRI) PD153035 on terminal differentiation of normal human epidermal keratinocytes (NHEKs). Cells treated with SB showed increased expression of the levels of mRNA and protein of the differentiation markers filaggrin and transglutaminase 1. Co-treatment with EGF significantly blunted these effects of SB. Combined treatment with SB and PD153035 alleviated these inhibitory actions of EGF, resulting in improved effects of decreased cell growth and increased terminal differentiation, relative to the individual treatments. These results indicate that the combined use of a differentiation-promoting agent and an EGFR inhibitor may offer an additional approach to the management of hyperproliferative skin diseases. PMID:24451036

Carrion, Sandra Leon; Sutter, Carrie Hayes; Sutter, Thomas R.

2014-01-01

197

Activated protein C: A regulator of human skin epidermal keratinocyte function  

PubMed Central

Activated protein C (APC) is a physiological anticoagulant, derived from its precursor protein C (PC). Independent of its anticoagulation, APC possesses strong anti-inflammatory, anti-apoptotic and barrier protective properties which appear to be protective in a number of disorders including chronic wound healing. The epidermis is the outermost skin layer and provides the first line of defence against the external environment. Keratinocytes are the most predominant cells in the epidermis and play a critical role in maintaining epidermal barrier function. PC/APC and its receptor, endothelial protein C receptor (EPCR), once thought to be restricted to the endothelium, are abundantly expressed by skin epidermal keratinocytes. These cells respond to APC by upregulating proliferation, migration and matrix metalloproteinase-2 activity and inhibiting apoptosis/inflammation leading to a wound healing phenotype. APC also increases barrier function of keratinocyte monolayers by promoting the expression of tight junction proteins and re-distributing them to cell-cell contacts. These cytoprotective properties of APC are mediated through EPCR, protease-activated receptors, epidermal growth factor receptor or Tie2. Future preventive and therapeutic uses of APC in skin disorders associated with disruption of barrier function and inflammation look promising. This review will focus on APC’s function in skin epidermis/keratinocytes and its therapeutical potential in skin inflammatory conditions. PMID:24921007

McKelvey, Kelly; Jackson, Christopher John; Xue, Meilang

2014-01-01

198

Luteolin Inhibits Human Keratinocyte Activation and Decreases NF-?B Induction That Is Increased in Psoriatic Skin  

PubMed Central

Psoriasis (Ps) is an autoimmune disease characterized by keratinocyte hyperproliferation and chronic inflammation, with increased expression of tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF). Anti-TNF biologic agents are effective in treating Ps, but are associated with increased risk of infections and blood malignancies. Moreover, keratinocyte hyperproliferation and activation have yet to be addressed. Flavonoids, such as luteolin, are natural compounds with potent anti-inflammatory properties, but their actions on keratinocytes remain unknown. We show that TNF (50 ng/mL) triggers significant production of inflammatory mediators interleukin-6, interleukin-8 and VEGF from both human HaCaT and primary keratinocytes. Pretreatment with the flavonoid luteolin (10–100 µM) significantly inhibits mRNA expression and release of all three mediators in a concentration-dependent manner. More importantly, luteolin decreases TNF-induced phosphorylation, nuclear translocation and DNA binding of the nuclear factor-kappa B (NF-?B) typically involved in inflammatory mediator transcription. We also report that luteolin reduces TNF-induced mRNA expression of two genes (NFKB1 and RELA) encoding two NF-?B subunits (NF-?B p50 and NF-?B p65, respectively). Interestingly, we show that gene expression of RELA is increased in human psoriatic skin. Keratinocyte proliferation, which is a characteristic feature of psoriatic skin, is effectively reduced by luteolin in HaCaT cells, but not in primary keratinocytes. Finally, luteolin does not affect intracellular ATP production or viability. Appropriate formulations of luteolin and related flavones may be promising candidates to be developed into local and systemic treatments for Ps and other inflammatory skin diseases. PMID:24587411

Weng, Zuyi; Patel, Arti B.; Vasiadi, Magdalini; Therianou, Anastasia; Theoharides, Theoharis C.

2014-01-01

199

Insulin-like growth factors and neoplasia  

Microsoft Academic Search

The insulin-like growth factor 1 (IGF1) signalling pathway has important roles in regulating cellular proliferation and apoptosis. Converging results from epidemiological research and in vivo carcinogenesis models indicate that high levels of circulating IGF1 are associated with increased risk of several common cancers. Ongoing research seeks to clarify the mechanisms underlying these observations and to determine the extent to which

Eva S. Schernhammer; Susan E. Hankinson; Michael N. Pollak

2004-01-01

200

HEMATOPOIETIC GROWTH FACTORS AND ACUTE MYELOID LEUKEMIA  

Microsoft Academic Search

affinity. When the ligands are added to cultures of AML cells, induction of metabolic and cell cycle activation appears. In some cases AML cells may mature towards terminally differentiated cells in response to cytokine stimulation. When AML cells stimulated with hematopoietic growth factors are subjected to chemotherapy in vitro, cell killing may be considerably enhanced.(1) These observations have been a

B. Löwenberg

201

Fibroblast growth factor signaling in the vasculature.  

PubMed

Despite their discovery as angiogenic factors and mitogens for endothelial cells more than 30 years ago, much remains to be determined about the role of fibroblast growth factors (FGFs) and their receptors in vascular development, homeostasis, and disease. In vitro studies show that members of the FGF family stimulate growth, migration, and sprouting of endothelial cells, and growth, migration, and phenotypic plasticity of vascular smooth muscle cells. Recent studies have revealed important roles for FGFs and their receptors in the regulation of endothelial cell sprouting and vascular homeostasis in vivo. Furthermore, recent work has revealed roles for FGFs in atherosclerosis, vascular calcification, and vascular dysfunction. The large number of FGFs and their receptors expressed in endothelial and vascular smooth muscle cells complicates these studies. In this review, we summarize recent studies in which new and unanticipated roles for FGFs and their receptors in the vasculature have been revealed. PMID:25813213

Yang, Xuehui; Liaw, Lucy; Prudovsky, Igor; Brooks, Peter C; Vary, Calvin; Oxburgh, Leif; Friesel, Robert

2015-06-01

202

Growth factors in ulcer healing: Lessons from recent studies  

Microsoft Academic Search

Growth factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and more recently vascular endothelial growth factor (VEGF) have been used extensively to heal experimental gastric, duodenal and colonic ulcers in animal models. Encouraging results have been reported in clinical trials with EGF and bFGF. Since our laboratory has been involved with the

Sandor Szabo; Áron Vincze

2000-01-01

203

Nerve Growth Factor and Diabetic Neuropathy  

PubMed Central

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50–90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium. PMID:14668049

Vinik, Aaron

2003-01-01

204

Binding of epidermal growth factor and insulin-like growth factor I in human myometrium and leiomyomata  

SciTech Connect

Samples of uterine myometrium and leiomyoma from 11 women were analyzed for the presence of epidermal growth factor receptors and insulin-like growth factor I receptors. In addition, the content of soluble insulin-like growth factor binding protein (IGF-BP/PP12) was measured in the tissue cytosols. Cell membrane preparations of myoma tissue bound significantly more insulin-like growth factor I than did those of adjacent normal myometrium, whereas myoma tissue bound less epidermal growth factor than did the normal myometrium. The differences in both insulin-like growth factor I and epidermal growth factor binding were due to changes in receptor concentration rather than to alterations in receptor affinity. Neither myoma nor myometrial tissue contained detectable levels of insulin-like growth factor binding protein. The changes in epidermal growth factor and insulin-like growth factor I binding to the myometrium may play a role in the pathogenesis of uterine leiomyomata.

Tommola, P.; Pekonen, F.; Rutanen, E.M. (Minerva Institute for Medical Research, Kauniainen (Finland))

1989-10-01

205

Altered (/sup 125/I)epidermal growth factor binding and receptor distribution in psoriasis  

SciTech Connect

Stimulation of growth and differentiation of human epidermis by epidermal growth factor (EGF) is mediated by its binding to specific receptors. Whether EGF receptors primarily mediate cell division or differentiation in hyperproliferative disease such as psoriasis vulgaris is unclear. To study the pathogenesis of psoriasis, 4-mm2 punch biopsy specimens of normal, uninvolved, and involved psoriatic skin were assayed for EGF receptors by autoradiographic, immunohistochemical, and biochemical methods. Using autoradiographic and immunohistochemical methods, basal keratinocytes were found to contain the greatest number of EGF binding sites and immunoreactive receptors as compared to the upper layers of the epidermis in both normal epidermis and psoriatic skin. No EGF receptor differences between normal and psoriatic epidermis were observed in this layer. In the upper layers of the epidermis, a 2-fold increase in EGF binding capacity was observed in psoriatic skin as compared with normal thin or thick skin. Biochemical methods indicated that (/sup 125/I)EGF binding was increased in psoriatic epidermis as compared with similar thickness normal epidermis when measured on a protein basis. Epidermal growth factor was shown to increase phosphorylation of the EGF receptor in skin. EGF receptors retained in the nonmitotic stratum spinosum and parakeratotic stratum corneum may reflect the incomplete, abnormal differentiation that occurs in active psoriatic lesions. Alternatively, retained EGF receptors may play a direct role in inhibiting cellular differentiation in the suprabasal layers.

Nanney, L.B.; Stoscheck, C.M.; Magid, M.; King, L.E. Jr.

1986-03-01

206

STIMULATION OF PIG GROWTH PERFORMANCE BY PORCINE GROWTH HORMONE AND GROWTH HORMONE-RELEASING FACTOR 1  

Microsoft Academic Search

The current study was undertaken to determine the effects of human growth hormone-releasing factor (hpGRF-(1-44)-NH2) on growth performance in pigs and whether this response was com- parable to exogenous porcine growth hormone (pGH) treatment. Preliminary studies were con- ducted to determine if GRF increased plasma GH concentration after iv and im injection and the nature of the dose response. Growth

T. D. Etherton; J. P. Wiggins; C. S. Chung; C. M. Evock; J. F. Rebhun; P. E. Walton

207

Distinct Effects of Different Phosphatidylglycerol Species on Mouse Keratinocyte Proliferation  

PubMed Central

We have previously shown that liposomes composed of egg-derived phosphatidylglycerol (PG), with a mixed fatty acid composition (comprising mainly palmitate and oleate), inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16?0/20?4), palmitoyl-linoleoyl-PG (16?0/18?2), dilinoleoyl-PG (18?2/18?2) and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16?0/18?1) and dioleoyl-PG (18?1/18?1) were especially effective proproliferative PG species. This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that these different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocyte proliferation. Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation. PMID:25233484

Xie, Ding; Seremwe, Mutsa; Edwards, John G.; Podolsky, Robert; Bollag, Wendy B.

2014-01-01

208

Hepatocyte growth factor/scatter factor-induced intracellular signalling  

PubMed Central

Hepatocyte growth factor (HGF) identical to scatter factor (SF) is a glycoprotein involved in the development of a number of cellular phenotypes, including proliferation, mitogenesis, formation of branching tubules and, in the case of tumour cells, invasion and metastasis. This fascinating cytokine transduces its activities via its receptor encoded by the c-met oncogene, coupled to a number of transducers integrating the HGF/SF signal to the cytosol and the nucleus. The downstream transducers coupled to HGF/MET, most of which participate in overlapping pathways, determine the development of the cell's phenotype, which in most cell types is dual. PMID:10718861

Stuart, Katherine A; Riordan, Stephen M; Lidder, Sukhwinderjit; Crostella, Luca; Williams, Roger; Skouteris, George G

2000-01-01

209

Transforming Growth Factor-? in Cancer Therapy  

Microsoft Academic Search

Several transforming growth factor-? (TGF-?) signaling pathway proteins undergo proteasomal degradation. Controlled proteasomal\\u000a degradation provides a means for the cell to time and fine-tune the duration of both positive and negative physiological signals.\\u000a Importantly, this physiological control appears to be aberrant in for example tumor cells carrying mutations of the Smad signaling\\u000a molecules. We summarize here the recent striking observations

Arja Band; Marikki Laiho

210

Growth Factors and Tension-Induced Skeletal Muscle Growth  

NASA Technical Reports Server (NTRS)

The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we have performed experiments to determine whether mechanical stimulation of cultured avian muscle cells alters their response to anabolic steroids or glucocorticoids. In static cultures, testosterone had no effect on muscle cell growth, but 5alpha-dihydrotestosterone and the synthetic steroid stanozolol increased cell growth by up to 18% and 30%, respectively, after a three day exposure. We completed development of a new IBM-based mechanical cell stimulator system to provide greater flexibility in operating and monitoring our experiments. Our previous long term studies on myofiber growth were designed around a perfusion system of our own design. We have recently changed to performing these studies using a modified CELLCO cartridge bioreactor system Z since it has been certified as the ground-based model for the Shuttle's Space Tissue Loss (STL) F= Cell Culture Module. The current goals of this aspect of the project are three fold: 1) to design a Z cell culture system for studying avian skeletal myofiber atrophy on the Shuttle and Space Station; 0 2) to expand the use of bioreactors to cells which do not grow in either suspension or attached to the hollow fibers; and 3) to combine the bioreactor system with our computerized mechanical cell stimulator to have a better in vitro model to study tension/gravity/stretch regulation of skeletal muscle size. Preliminary studies also reported on involved : (1) how release of tension can induce rapid atrophy of tissues cultured avian skeletal muscle cells, and (2) a mechanism to transfer and maintain avian skeletal muscle organoids in modified cartridges in the Space Tissue Loss Module.

Vandenburgh, Herman H.

1994-01-01

211

PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK)  

SciTech Connect

Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24 days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism. -- Highlights: ? Human immortal (HaCaT) and primary (NFK) keratinocytes were exposed to PCB153. ? PCB153 significantly reduced telomerase activity and telomere length in HaCaT. ? No effect on telomere length and telomerase activity was found in NFK. ? Increased intracellular superoxide levels and reduced cell growth was seen in both. ? PCB153 may damage telomerase expressing cells like stem cells.

Senthilkumar, P.K. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States)] [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Robertson, L.W. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States) [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA (United States); Ludewig, G., E-mail: Gabriele-ludewig@uiowa.edu [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA (United States)

2012-02-15

212

Activated keratinocytes in the epidermis of hypertrophic scars.  

PubMed Central

The etiology of hypertrophic scarring, a pathological end point of wound healing, is unknown. The scars most commonly occur when epithelialization has been delayed during, for example, the healing of deep dermal burn wounds. Hypertrophic scars are conventionally described as a dermal pathology in which the epidermis has only a passive role. In this study, the expression of keratin intermediate filament proteins and filaggrin has been investigated in the epidermis of hypertrophic scars and site-matched controls from the same patients. Hypertrophic scar epidermis was found to express the hyperproliferative keratins K6 and K16 in interfollicular epidermis in association with K17 and precocious expression of filaggrin. K16 mRNA was localized by in situ hybridization using a highly specific cRNA probe. In contrast to the immunohistochemical location of K16 protein, the K16 mRNA was found to be expressed in the basal cell layer of normal skin. In hypertrophic scars the mRNA distribution corroborated the abnormal K16 protein distribution. These results suggest the keratinocytes in hypertrophic scar epidermis have entered an alternative differentiation pathway and are expressing an activated phenotype. Activated keratinocytes are a feature of the early stages of wound healing producing growth factors that influence fibroblasts, endothelial cells, and the inflammatory response. We propose that cellular mechanisms in the pathogenesis of hypertrophic scarring are more complex than isolated dermal phenomena. The persistence of activated keratinocytes in hypertrophic scar epidermis implicates abnormal epidermal-mesenchymal interactions. Images Figure 1 Figure 3 PMID:9588880

Machesney, M.; Tidman, N.; Waseem, A.; Kirby, L.; Leigh, I.

1998-01-01

213

Transforming growth factor-alpha secretion by epidermal growth factor-dependent human tumor cell lines.  

PubMed

Pairs of cell lines from spontaneous human tumors (cervical adenocarcinoma, melanoma, and synovial sarcoma) were established using serum-free culture conditions with and without exogenous epidermal growth factor (EGF). EGF-adapted cultures of melanoma and cervical adenocarcinoma origin secreted higher levels of bioactive transforming growth factor alpha (TGF-alpha) when compared to cultures maintained in the absence of EGF. Depletion of EGF for these EGF-adapted cultures resulted in growth arrest. In contrast, the sarcoma cell lines did not secrete TGF-alpha regardless of the culture conditions but EGF significantly stimulated proliferation of these cells in short-term assays. We show that exogenous EGF induces TGF-alpha production and supports proliferation of tumor cells of various tissue origin but is not essential for in vitro growth factor-deprived conditions. PMID:2285223

Singletary, S E; Williams, N N; Rodeck, U; Larry, L; Tucker, S; Spitzer, G; Herlyn, M

1990-01-01

214

Transcriptional Profiling of Ectoderm Specification to Keratinocyte Fate in Human Embryonic Stem Cells  

PubMed Central

In recent years, several studies have shed light into the processes that regulate epidermal specification and homeostasis. We previously showed that a broad-spectrum ?–secretase inhibitor DAPT promoted early keratinocyte specification in human embryonic stem cells triggered to undergo ectoderm specification. Here, we show that DAPT accelerates human embryonic stem cell differentiation and induces expression of the ectoderm protein AP2. Furthermore, we utilize RNA sequencing to identify several candidate regulators of ectoderm specification including those involved in epithelial and epidermal development in human embryonic stem cells. Genes associated with transcriptional regulation and growth factor activity are significantly enriched upon DAPT treatment during specification of human embryonic stem cells to the ectoderm lineage. The human ectoderm cell signature identified in this study contains several genes expressed in ectodermal and epithelial tissues. Importantly, these genes are also associated with skin disorders and ectodermal defects, providing a platform for understanding the biology of human epidermal keratinocyte development under diseased and homeostatic conditions. PMID:25849374

Tadeu, Ana Mafalda Baptista; Lin, Samantha; Hou, Lin; Chung, Lisa; Zhong, Mei; Zhao, Hongyu; Horsley, Valerie

2015-01-01

215

Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair.  

PubMed

Significance: Angiogenesis, the growth of new blood vessels from existing vessels, is an important aspect of the repair process. Restoration of blood flow to damaged tissues provides oxygen and nutrients required to support the growth and function of reparative cells. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic growth factors in the skin, and the amount of VEGF present in a wound can significantly impact healing. Recent Advances: The activity of VEGF was once considered to be specific for endothelial cells lining the inside of blood vessels, partly because VEGF receptor (VEGFR) expression was believed to be restricted to endothelial cells. It is now known, however, that VEGFRs can be expressed by a variety of other cell types involved in wound repair. For example, keratinocytes and macrophages, which both carry out important functions during wound healing, express VEGFRs and are capable of responding directly to VEGF. Critical Issues: The mechanisms by which VEGF promotes angiogenesis are well established. Recent studies, however, indicate that VEGF can directly affect the activity of several nonendothelial cell types present in the skin. The implications of these extra-angiogenic effects of VEGF on wound repair are not yet known, but they suggest that this growth factor may play a more complex role during wound healing than previously believed. Future Directions: Despite the large number of studies focusing on VEGF and wound healing, it is clear that the current knowledge of how VEGF contributes to the repair of skin wounds is incomplete. Further research is needed to obtain a more comprehensive understanding of VEGF activities during the wound healing process. PMID:25302139

Johnson, Kelly E; Wilgus, Traci A

2014-10-01

216

The E5 Oncoprotein of Human Papillomavirus Type 16 Inhibits the Acidification of Endosomes in Human Keratinocytes  

Microsoft Academic Search

Thehumanpapillomavirustype16E5oncoproteinpossessesmitogenicactivitythatactssynergisticallywith epidermal growth factor (EGF) in human keratinocytes and inhibits the degradation of the EGF receptor in endosomal compartments after ligand-stimulated endocytosis. One potential explanation for these observa- tions is that E5 inhibits the acidification of endosomes. This may be mediated through the 16-kDa component ofthevacuolarproton-ATPase,sinceanimalandhumanpapillomavirusE5proteinsbindthissubunitprotein. Using a ratio-imaging technique to determine endosomal pH, we found that the acidification of

SAMUEL W. STRAIGHT; BRIAN HERMAN; ANDDENNIS J. MCCANCE

1995-01-01

217

Reprogramming human adipose tissue stem cells using epidermal keratinocyte extracts  

PubMed Central

Human adipose tissue stem cells (ATSCs) can differentiate into various types of cell in response to lineage-specific induction factors. Reprogramming cells using nuclear and cytoplasmic extracts derived from another type of somatic cell is an effective method of producing specific types of differentiated cell. In the present study, the ability of reprogrammed ATSCs to acquire epidermal keratinocyte properties following transient exposure to epidermal keratinocyte extracts was demonstrated. Reversibly permeabilized ATSCs were incubated for 1 h in nuclear and cytoplasmic extracts from epidermal keratinocytes, resealed with CaCl2 and cultured. ATSC reprogramming is demonstrated by nuclear uptake of epidermal keratinocyte extracts. After one week of exposure to extracts, ATSCs underwent changes in cell morphology, cell-specific genes were activated, and epidermal keratinocyte markers including K19 and K1/K10 (markers of stem cells and terminally differentiated keratinocytes, respectively) were expressed. This study indicates that the reprogramming of ATSCs using nuclear and cytoplasmic extracts from epidermal keratinocytes is a viable option for the production of specific types of cell. PMID:25333210

XIE, FENG; TANG, XINJIE; ZHANG, QUN; DENG, CHENLIANG

2015-01-01

218

The structural biology of growth factor receptor activation.  

PubMed

Stimulation of cells by growth factors triggers cascades of signalling that result in cellular responses such as growth, differentiation, migration and survival. Many growth factors signal through receptor tyrosine kinases, leading to dimerization, trans-phosphorylation and activation of tyrosine kinases that phosphorylate components further downstream of the signal transduction cascade. Using insulin-like growth factor, nerve growth factor, hepatocyte growth factor and fibroblast growth factor as examples, we show that the globular architecture of the growth factors is essential for receptor binding. We describe how nerve growth factor (NGF) is a symmetrical dimer that binds four storage proteins (two alpha-NGF and two gamma-NGF) to give a symmetrical hetero-hexameric 7SNGF organised around the beta-NGF dimer. It binds the extracellular domains of two receptor molecules in a similar way, so dimerising the receptor. Hepatocyte growth factor/scatter factor (HGF/SF) probably binds its receptor as a dimer stabilised by interactions with heparan sulfate, and fibroblast growth factor (FGF) binds its receptor as a dimer cross-linked by heparan sulfate. Surprisingly, insulin and insulin-like growth factor (IGF) bind in the monomeric form to receptors that are already covalent dimers. We propose that, in general, weak binary interactions between growth factor and individual domains of receptors are enhanced by cooperative interactions with further receptor domains, and sometimes other components like heparan, to give rise to specific multi-protein/domain complexes. PMID:12646390

Harmer, Nicholas J; Chirgadze, Dima; Hyun Kim, Kyung; Pellegrini, Luca; Blundell, Tom L

2003-01-01

219

Elevation of cell cycle control proteins during spontaneous immortalization of human keratinocytes.  

PubMed Central

A human line of spontaneously immortalized keratinocytes (SIK cells) has been derived from ostensibly normal epidermis and has proven useful in dissecting molecular changes associated with immortalization. The original cultures had a normal karyotype and a colony forming efficiency of approximately 3% through 10 passages. At passage 15, after which normal strains ordinarily senesce, these cells continued vigorous growth and gradually increased in colony forming efficiency, stabilizing at approximately 30% by passage 40. During the early stage of increasing colony forming efficiency, the cells acquired a single i(6p) chromosomal aberration and 5- to 10-fold increases in expression of the cell-cycle control proteins cyclin A, cyclin B, and p34cdc2. Additional chromosomal aberrations accumulated at later passages (i(8q) and +7), but the i(6p) and the increased expression of cell-cycle proteins were maintained, raising the possibility that these features were important for immortalization. Regulation of cell growth and differentiation in the cultures appeared minimally altered compared with normal keratinocytes as judged by their microscopic appearance and generation of abortive colonies, sensitivity to growth suppression by transforming growth factor-beta and tetradecanoylphorbol acetate, and dependence upon epidermal growth factor for progressive growth. Images PMID:8443416

Rice, R H; Steinmann, K E; deGraffenried, L A; Qin, Q; Taylor, N; Schlegel, R

1993-01-01

220

Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth  

Microsoft Academic Search

Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET proto- oncogene. Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190 MEt) made of a 50 kD (o0 subunit disulfide linked to a 145-kD

F. Bussolino; M. E Di Renzo; M. Ziche; E. Bocchietto; M. Olivero; L. Naldini; G. Gaudino; L. Tamagnone; A. Coffer; P. M. Comoglio

1992-01-01

221

Novel method for isolating human melanoblasts from keratinocyte culture.  

PubMed

The characterization of melanoblasts is important for understanding their in vivo development, melanoma formation, and pigment-related disorders. However, no methods have been reported for the isolation of melanoblasts from human skin. Using a 'calcium-pulse' technique, involving the differentiation of human keratinocytes with high calcium and the subsequent spontaneous separation of the epidermal sheets, we effectively isolated human melanoblasts (keratinocyte-adapted melanoblasts, KaMBs) from keratinocyte culture. The KaMBs expressed early melanogenesis-related genes, including BRN2, which is a known melanoblast marker. Moreover, the KaMBs displayed much higher proliferative and growth capacities than the primary melanocytes. Considering that keratinocytes might provide an in vivo-like environment for KaMBs during isolation and in vitro culture, the 'calcium-pulse' technique offers an unprecedented, easy, and efficient method for the isolation of human melanoblasts, retaining the original characteristics of these cells. PMID:24460991

Cho, Eun-Gyung; Bin, Bum-Ho; Choi, Hyunjung; Park, Phil June; Kang, Hak Hee; Lee, Tae Ryong

2014-05-01

222

The epithelial-mesenchymal transition induced by keratinocyte growth conditions is overcome by E6 and E7 from HPV16, but not HPV8 and HPV38: Characterization of global transcription profiles  

SciTech Connect

The aim of this study was to evaluate the growth properties of primary human keratinocytes expressing E6 and E7 proteins, which are from either the beta- or alpha-genotypes, under different culture conditions. We demonstrated that keratinocytes expressing E6 and E7, from both HPV8 and 38, irreversibly underwent the epithelial-mesenchymal transition (EMT) when grown on plastic with FAD medium (F12/DMEM/5%FBS). Expression of E6/E7 from HPV16 was capable of fully overcoming the FAD-induced EMT. Immortalization was only observed in HPV16-transduced cell lines, while the more proliferating phenotype of both KerHPV8 and 38 was mainly related to FAD-induced EMT. Microarray analysis of exponentially growing cells identified 146 cellular genes that were differentially regulated in HPV16 compared to HPV8- and 38-transduced cells. A large accumulation of transcripts associated with epidermal development and differentiation was observed in HPV16-transduced cells, whereas transcripts of genes involved in the extracellular matrix, multicellular organismal processes, and inflammatory response were affected in HPV8 and 38-transduced cells.

Azzimonti, Barbara; Dell'Oste, Valentina; Borgogna, Cinzia; Mondini, Michele [Department of Clinical and Experimental Medicine, Medical School of Novara, via Solaroli 17, 28100 Novara (Italy); Gugliesi, Francesca [Department of Public Health and Microbiology, Medical School of Turin, via Santena 9, 10126 Torino (Italy); De Andrea, Marco [Department of Clinical and Experimental Medicine, Medical School of Novara, via Solaroli 17, 28100 Novara (Italy); Department of Public Health and Microbiology, Medical School of Turin, via Santena 9, 10126 Torino (Italy); Chiorino, Giovanna; Scatolini, Maria; Ghimenti, Chiara [Cancer Genomics Lab Fondo Edo Tempia, via Malta 3, 13900 Biella (Italy); Landolfo, Santo [Department of Public Health and Microbiology, Medical School of Turin, via Santena 9, 10126 Torino (Italy); Gariglio, Marisa, E-mail: gariglio@med.unipmn.i [Department of Clinical and Experimental Medicine, Medical School of Novara, via Solaroli 17, 28100 Novara (Italy)

2009-06-05

223

Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements  

SciTech Connect

Human papilloma virus (HPV) types 16 and 18 are most commonly associated with cervical carcinoma in patients and induce immortalization of human keratinocytes in culture. HPV has not been associated with breast cancer. This report describes the immortalization of normal human mammary epithelial cells (76N) by plasmid pHPV18 or pHPV16, each containing the linearized viral genome. Transfectants were grown continuously for more than 60 passages, whereas 76N cells senesce after 18-20 passages. The transfectants also differ from 76N cells in cloning in a completely defined medium called D2 and growing a minimally supplemented defined medium (D3) containing epidermal growth factor. All transfectant tested contain integrated HPV DNA, express HPV RNA, and produce HPV E7 protein. HPV transfectants do not form tumors in a nude mouse assay. It is concluded that products of the HPV genome induce immortalization of human breast epithelial cells and reduce their growth factor requirements. This result raises the possibility that HPV might be involved in breast cancer. Furthermore, other tissue-specific primary epithelial cells that are presently difficult to grown and investigate may also be immortalized by HPV.

Band, V.; Zajchowski, D.; Kulesa, V.; Sager, R. (Dana-Farber Cancer Institute, Boston, MA (USA))

1990-01-01

224

Economic growth as the limiting factor for wildlife conservation  

Microsoft Academic Search

The concept of limiting factor includes the lack of welfare factors and the presence of decimating factors. Originally applied to populations and species, the concept may also be applied to wildlife in the aggregate. Because the decimating factor of economic growth eliminates welfare factors for virtually all imperiled species via the principle of competitive exclusion, economic growth may be classified

Brian Czech

2000-01-01

225

The effects of human keratinocyte coculture on human adipose-derived stem cells.  

PubMed

The potential for adipose-derived stem cells to differentiate into keratinocyte-like cells has recently been receiving attention, stemming from the hypothesis that a bioengineered skin may be manufactured from these readily available mesenchymal stem cells. This study was conducted to evaluate the influence of human keratinocyte non-contact coculture on hADSCs. Human epidermal keratinocytes and hADSCs obtained by lipoaspiration were cultured in keratinogenic growth media, which were divided into the following groups: human adipose-derived stem cell (hADSC) monoculture, non-contact coculture of hADSCs and human keratinocytes and keratinocyte monoculture. Cell proliferation was assessed, and keratogenicity was analysed through immunocytochemistry and polymerase chain reaction of early, intermediate and late keratogenic markers. hADSCs cocultured with keratinocytes displayed enhanced proliferation compared with the monoculture group. After a 7-day coculture period, immunohistochemistry and polymerase chain reaction findings revealed the presence of specific keratinocyte markers in the coculture group. This study demonstrates that hADSCs cocultured with keratinocytes have the capacity to transdifferentiate into keratinocyte lineage cells, and suggests that adipose tissue may be a source of keratinocytes that may further be used in structuring the bioengineered skin. PMID:25091634

Seo, Bommie F; Kim, Ki J; Kim, Min K; Rhie, Jong W

2014-08-01

226

Neuronal growth factors, neurotrophins and memory deficiency.  

PubMed

CNS and PNS ontogenesis are regulated by various proteic factors, and the best characterized of which still remains Nerve Growth Factor (NGF), a molecule exerting trophic, tropic (i.e. directing growing axons toward NGF-releasing target tissue) and differentiative effects on a number of neural and non-neural (e.g. mast-cells) cell lines. Other Growth Factors (GFs), called 'neurotrophins' (BDNF, NT-3, NT-4, NT-5) also exert similar effects on specific neural cell population. Other GFs (EGF, TGFs, IGFs, FGFs) share these growth-promoting properties with the neurotrophins. NGF appears to regulate specifically the postnatal maturation of the CNS cholinergics in altricial rodents. In adults, cholinergic neurons show retrograde transport for NGF and degeneration of cholinergic neurons after fimbria-fornix transection is prevented by NGF infusion, suggesting a role for NGF in maintaining normal cholinergic function in adulthood. However, peptidergic neurons (e.g. SP-positive cells) seem also to be influenced by perinatal NGF administration, indicating that the spectrum of NGF actions is wider than previously reported. In recent years we investigated the role of NGF in controlling behavioural maturation in the early postnatal period by comparing NGF effects with those of related and non-related neurotrophins (EGF, basic FGF, IGF-1, Transforming GF-alfa). We found that a single intracerebral injection of NGF accelerates cholinergic maturation on postnatal day (PND) 20, as shown by the enhanced reactivity to the muscarinic blocker scopolamine. Scopolamine-induced hyperactivity, normally appearing at the end of the third week, emerges already at PND 5 following NGF administration on PND 2 and 4.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7755882

Calamandrei, G; Alleva, E

1995-01-23

227

Transforming growth factor-beta and breast cancer: Tumor promoting effects of transforming growth factor-?  

Microsoft Academic Search

The transforming growth factor (TGF)-?s are potent growth inhibitors of normal epithelial cells. In established tumor cell systems, however, the preponderant experimental evidence suggests that TGF-?s can foster tumor-host interactions that indirectly support the viability and\\/or progression of cancer cells. The timing of this 'TGF-? switch' during the progressive transformation of epithelial cells is not clear. More recent evidence also

Nancy Dumont; Carlos L Arteaga

2000-01-01

228

Proliferative Defects in Dyskeratosis Congenita Skin Keratinocytes are Corrected by Expression of the Telomerase Reverse Transcriptase, TERT, or by Activation of Endogenous Telomerase through Expression of Papillomavirus E6/E7 or the Telomerase RNA Component, TERC  

PubMed Central

Dyskeratosis congenita (DC) is characterized by the triad of reticulate skin pigmentation, nail dystrophy, and leukoplakia. Epidermal atrophy, hair growth defects, bone marrow failure, and increased risk of cancer are also common in DC patients. DC is caused by mutations in genes encoding for telomerase complex factors. Although there is an association of epidermal abnormalities with DC, epidermal cells from DC donors have not been previously characterized. We have isolated skin keratinocytes from affected members of a family with an autosomal dominant form of DC that is due to a mutation in the RNA component of telomerase, TERC. Here we demonstrate that, similar to DC fibroblasts from these donors, DC keratinocytes have short telomeres and a short lifespan. DC keratinocytes also exhibited impaired colony forming efficiency and migration capacity. Exogenous expression of the reverse transcriptase component of telomerase, TERT, activated telomerase levels to half that of TERT expressing normal cells and maintained telomeres at a short length with concomitant extension of lifespan. Unlike fibroblasts, transduction of human papillomavirus type 16 E6/E7 genes into DC keratinocytes activated telomerase to half that of E6/E7 expressing normal cells, and robust proliferation was observed. While expression of TERC has no measurable effect on telomerase in fibroblasts, expression of TERC in keratinocytes upregulated telomerase activity and, rarely, allowed rescue of proliferative defects. Our results point to important differences between DC fibroblasts and keratinocytes and show, for the first time, that expression of TERC can increase the lifespan of primary human epithelial cells. PMID:19558498

Gourronc, Francoise A.; Robertson, Mckaylee M.; Herrig, Annie K.; Lansdorp, Peter M.; Goldman, Frederick D.; Klingelhutz, Aloysius J.

2010-01-01

229

Integrin ?6?4 and TRPV1 channel coordinately regulate directional keratinocyte migration.  

PubMed

The directional migration of epithelial cells is crucial for wound healing. Among integrins, a family of cell adhesion receptors, integrin ?4 has been assumed to be a promigratory factor, in addition to its role in stable adhesion. In turn, Ca(2+) signaling is also a key coordinator of migration. Keratinocytes reportedly express transient receptor potential vanilloid channels (TRPV1); however, the function of these channels as a regulator of intracellular Ca(2+) level in cell migration has remained uncharacterized. In the present study, we investigated the role of TRPV1 in directional migration related to integrin ?4 using a scratch wound assay on a confluent monolayer sheet of murine keratinocytes (Pam212 cells). Double immunofluorescence staining revealed the de novo expression of integrin ?4 and TRPV1 in migrating cells at the wound edge in response to scratch wounding, and both expression levels were almost matched. Epidermal growth factor (EGF) not only promoted keratinocyte migration, but also caused the further up-regulation of both integrin ?4 and TRPV1. In addition, the knockdown of the integrin ?4 or TRPV1 gene significantly impeded wound closure. The TRPV1 agonist capsaicin significantly promoted migration, while a selective TRPV1 antagonist inhibited it. The gene knockdown of TRPV1 inhibited the expression of the integrin ?4 gene and that of ?4 protein in migrating cells. These findings suggest that TRPV1 may stimulate directional migration directly by eliciting a Ca(2+) signal or indirectly via integrin ?4 expression. PMID:25637531

Miyazaki, Ayako; Ohkubo, Tsuyako; Hatta, Mitsutoki; Ishikawa, Hiroyuki; Yamazaki, Jun

2015-02-27

230

Immortalization of normal human gingival keratinocytes and cytological and cytogenetic characterization of the cells  

Microsoft Academic Search

Most in vitro studies of oral carcinogenesis in human cells are carried out with oral keratinocytes immortalized by human\\u000a papillomavirus type 16 DNA. However, because various etiological factors for oral cancer are known, it is important to establish\\u000a new human keratinocyte cell lines useful for studying the mechanism of oral carcinogenesis. Normal human gingival keratinocytes\\u000a in secondary cultures grown in

Chikahiro Kubo; Takeo W. Tsutsui; Yukiko Tamura; Shin-ichi Kumakura; Takeki Tsutsui

2009-01-01

231

Sequential Delivery of Basic Fibroblast Growth Factor and Platelet-Derived Growth Factor for Angiogenesis  

PubMed Central

An externally regulated delivery model that permits temporal separation of multiple angiogenic factors was used for the delivery of basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). While bFGF plays a significant role in the sprouting of new capillaries, PDGF plays a role in the recruitment of mural cells, which stabilize neovessels. However, these two factors have been shown to inhibit each other, when presented together. Using the externally regulated model, sequential delivery of bFGF and PDGF led to not only increased endothelial cell migration, but also endothelial cell and vascular pericyte colocalization. More importantly, this delivery strategy was able to induce red blood cell-filled neovessels, suggesting integration of angiogenesis with the existing vasculature. PMID:21142700

Tengood, Jillian E.; Ridenour, Ryan; Brodsky, Ross; Russell, Alan J.

2011-01-01

232

Scatter factor\\/hepatocyte growth factor is essential for liver development  

Microsoft Academic Search

POLYPEPTIDE growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor1-3\\/hepatocyte growth factor4,5 (SF\\/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood

Claudia Schmidt; Friedhelm Bladt; Stefanie Goedecke; Volker Brinkmann; Wolfgang Zschiesche; Melanie Sharpe; Ermanno Gherardi; Carmen Birchmeler

1995-01-01

233

Matrix metalloproteinase inhibition delays wound healing and blocks latent transforming growth factor-?1 promoted myofibroblast formation and function  

PubMed Central

The ability to regulate wound contraction is critical for wound healing as well as for pathological contractures. Matrix metalloproteinases (MMPs) have been demonstrated to be obligatory for normal wound healing. This study examined the effect the broad-spectrum MMP inhibitor BB-94 has when applied topically to full-thickness skin excisional wounds in rats and its ability to inhibit the promotion of myofibroblast formation and function by latent transforming-growth factor-?1 (TGF-?1). BB-94 delayed wound contraction, as well as all other associated aspects of wound healing examined, including myofibroblast formation, stromal cell proliferation, blood vessel formation, and epithelial wound coverage. Interestingly, BB-94 dramatically increased the level of latent and active MMP-9. The increased levels of active MMP-9 may eventually overcome the ability of BB-94 to inhibit this MMP and may explain why wound contraction and other associated events of wound healing were only delayed and not completely inhibited. BB-94 was also found to inhibit the ability of latent TGF-?1 to promote the formation and function of myofibroblasts. These results suggest that BB-94 could delay wound closure through a two-fold mechanism; by blocking keratinocyte migration and thereby blocking necessary keratinocyte-fibroblast interactions needed for myofibroblast formation and by inhibiting the activation of latent TGF-?1. PMID:20409148

Mirastschijski, Ursula; Schnabel, Reinhild; Claes, Juliane; Schneider, Wolfgang; Ågren, Magnus S.; Haaksma, Carol; Tomasek, James J.

2010-01-01

234

Transforming Growth Factor-?1 Induces Vascular Endothelial Growth Factor Expression in Murine Proximal Tubular Epithelial Cells  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that promotes angiogenesis, vasculogenesis, and increases vascular permeability. VEGF is expressed in renal tubular epithelial cells and urinary VEGF excretion is increased in various glomerular disorders. However, the mechanisms underlying expression of VEGF in renal tubular epithelial cells have not been fully elucidated. In the present study, we attempted

Shinji Kitamura; Yohei Maeshima; Takeshi Sugaya; Hitoshi Sugiyama; Yasushi Yamasaki; Hirofumi Makino

2003-01-01

235

Nerve growth factor interactions with mast cells.  

PubMed

Neuropeptides are involved in neurogenic inflammation where there is vasodilation and plasma protein extravasion in response to this stimulus. Nerve growth factor (NGF), identified by Rita Levi Montalcini, is a neurotrophin family compound which is important for survival of nociceptive neurons during their development. Therefore, NGF is an important neuropeptide which mediates the development and functions of the central and peripheral nervous system. It also exerts its proinflammatory action, not only on mast cells but also in B and T cells, neutrophils and eosinophils. Human mast cells can be activated by neuropeptides to release potent mediators of inflammation, and they are found throughout the body, especially near blood vessels, epithelial tissue and nerves. Mast cells generate and release NGF after degranulation and they are involved in iperalgesia, neuroimmune interactions and tissue inflammation. NGF is also a potent degranulation factor for mast cells in vitro and in vivo, promoting differentiation and maturation of these cells and their precursor, acting as a co-factor with interleukin-3. In conclusion, these studies are focused on cross-talk between neuropeptide NGF and inflammatory mast cells. PMID:24674674

Kritas, S K; Caraffa, A; Antinolfi, P; Saggini, A; Pantalone, A; Rosati, M; Tei, M; Speziali, A; Saggini, R; Pandolfi, F; Cerulli, G; Conti, P

2014-01-01

236

Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate  

PubMed Central

Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, causes increased levels of tyrosine phosphorylation and blocks, at noncytotoxic concentrations, the differentiative response of rat pheochromocytoma (PC12) cells to beta-nerve growth factor (beta NGF) and basic fibroblast growth factor (bFGF) in a reversible manner. It also prevents growth factor-induced neurite proliferation in primed cells and causes the retraction of previously formed neurites, even in the presence of beta NGF or bFGF. It is equally effective in blocking neurite proliferation by 8-Br-cAMP. Zinc chloride and ammonium molybdate, two other inhibitors of tyrosine phosphatases, also cause parallel decreases in neurite proliferation. Orthovanadate generally reduces the transcription of immediate early response genes (TIS 8 and c-fos) and secondary response genes (ornithine decarboxylase (ODC), acetyl-cholinesterase (AChE) and SCG 10) induced by beta NGF, bFGF, EGF, and PMA, albeit in a variable fashion. There was no observed effect on the kinetics of expression as judged by TIS 8 induction by beta NGF and protein kinase C (PKC) downregulation did not change the levels of inhibition by orthovanadate seen in control cells. Orthovanadate does not affect the production of diacylglycerol induced by beta NGF or bFGF. These observations are consistent with the view that growth factor stimulation of differentiation in PC12 cells involves at least one other PKC independent pathway, and that cAMP and PMA (and their active analogs) activate tyrosine kinases (albeit probably secondarily), which are at least partially responsible for their actions. Although the exact site(s) of action of orthovanadate that lead to the inhibition of growth factor-induced neurite proliferation are unknown, the results presented suggest that it prolongs tyrosine phosphorylations by nonreceptor tyrosine kinases that act downstream from the receptor kinases. PMID:8468355

1993-01-01

237

Matrix control of transforming growth factor-? function  

PubMed Central

The cytokine transforming growth factor-beta (TGF-?) has multiple effects in both physiological and pathological conditions. TGF-? is secreted as part of a tripartite complex from which it must be released in order to bind to its receptor. Sequestration of latent TGF-? in the extracellular matrix (ECM) is crucial for proper mobilization of the latent cytokine and its activation. However, contrary to expectation, loss-of-function mutations in genes encoding certain matrix proteins that bind TGF-? yield elevated, rather than decreased, TGF-? levels, posing a ‘TGF-? paradox.’ In this review, we discuss recent findings concerning the relationship of TGF-?, ECM molecules, and latent TGF-? activation and propose a model to resolve the ‘TGF-? paradox.’ PMID:22923731

Horiguchi, Masahito; Ota, Mitsuhiko; Rifkin, Daniel B.

2012-01-01

238

Systems Biology of Vascular Endothelial Growth Factors  

PubMed Central

Several cytokine families have roles in development, maintenance and remodeling of the microcirculation. Of these, the VEGF family is one of the best studied and one of the most complex. Five VEGF ligand genes and five cell surface receptor genes are known in the human, and each of these may be transcribed as multiple splice isoforms to generate an extensive family of proteins, many of which are subject to further proteolytic processing. Using the VEGF family as an example, we describe the current knowledge of growth factor expression, processing and transport in vivo. Experimental studies and computational simulations are being used to measure and predict the activity of these molecules, and we describe avenues of research that seek to fill the remaining gaps in our understanding of VEGF family behavior. PMID:18608994

Mac Gabhann, Feilim; Popel, Aleksander S.

2009-01-01

239

Role of growth factors in the growth of normal and transformed cells  

Microsoft Academic Search

Growth factors play an important role in the growth of normal cells. However, their untimely and\\/or excess production leads to neoplastic transformation. The role of growth factors in the growth of normal cells was studied by investigating the mechanism of transmodulation of the cell surface EGF receptor number by protamine. Protamine increased the EGF stimulated mitogenic response in Swiss mouse

Lokeshwar

1989-01-01

240

The Fibroblast Growth Factor signaling pathway  

PubMed Central

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, PLC?, 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

Ornitz, David M; Itoh, Nobuyuki

2015-01-01

241

Effects of epidermal growth factor and transforming growth factor alpha on the function of wool follicles in culture  

Microsoft Academic Search

The development of a procedure to culture wool follicles from Merino sheep in serum-free conditions has enabled us to investigate\\u000a the actions of epidermal growth factor (EGF) and transforming growth factor alpha (TGF?) on follicle function, including fibre\\u000a growth. Follicles grown in the absence of growth factors maintained their anagen morphology for 6 days as determined by light\\u000a microscopy. During

J. J. Bond; P. C. Wynn; G. P. M. Moore

1996-01-01

242

Endorsement of Growth Factors in Experiential Training Groups  

ERIC Educational Resources Information Center

The purpose of this study was to identify student growth factors during a semester long Master's level group counseling class. Results indicated that 12 growth factors accounted for 86% of the total number of critical incidents that participants reported as influencing their personal growth and awareness during the group experience. Two other…

Kiweewa, John; Gilbride, Dennis; Luke, Melissa; Seward, Derek

2013-01-01

243

Prolonged Activation of ERK2 by Epidermal Growth Factor and Other Growth Factors Requires a Functional Insulin-Like Growth Factor 1 Receptor  

Microsoft Academic Search

We have investigated the activation of ERK2, a serine\\/threonine kinase necessary for transmission of mitogenic signals, in cells de- rived from mouse embryos homozygous for a null mutation of the insulin-like growth factor (IGF)-1R gene (R2 cells) and from wild-type littermates (W cells), respectively. Stimulation of quiescent W cells with IGF-1, epidermal growth factor (EGF), or with a combination growth

JENNIFER L. SWANTEK; RENATO BASERGA

1999-01-01

244

Platelet-derived growth factors and fibroblast growth factors are mitogens for rat Schwann cells  

PubMed Central

Rat sciatic nerve Schwann cells in culture respond to a limited range of mitogens, including glial growth factor, transforming growth factors beta-1 and beta-2 (TGF-beta 1, TGF-beta 2), some cell membrane- associated factors, and to agents such as cholera toxin and forskolin which raise intracellular levels of cAMP. These responses require the presence of FCS, which exhibits little or no mitogenic activity in the absence of other factors. However, we recently found that forskolin greatly potentiates the mitogenic signal from TGFs-beta 1 and beta 2, raising the possibility that cAMP might couple other factors to mitogenesis. We have therefore screened a range of candidate mitogens using DNA synthesis assays. Other than TGFs-beta and glial growth factor, none of the factors tested were mitogenic in the presence of 10% serum alone. With the addition of forskolin, however, porcine PDGF, human PDGF, acidic and basic FGF were potent mitogens for rat Schwann cells, stimulating DNA synthesis and increasing cell number. Cholera toxin and dibutyrylcyclicAMP, but not 1,9-dideoxyforskolin, can substitute for forskolin indicating that the mitogenic effect is mediated via adenylyl cyclase activation. Porcine PDGF gave half- maximal stimulation at 15 pM, and human PGDF an equivalent response at 1 nM. Basic FGF was half maximal at 5 pM, acidic FGF at 1 nM. The recognition of PDGFs and FGFs as mitogens for Schwann cells has many implications for the study of Schwann cell proliferation in the development and regeneration of nerves, and in Schwann cell tumorigenesis. PMID:2157720

1990-01-01

245

Connective Tissue Growth Factor: What's in a Name?  

Microsoft Academic Search

Connective tissue growth factor (CTGF) is a member of the recently described CCN gene family which contains CTGF itself, cyr61, nov, elm1, Cop1, and WISP-3. CTGF is transcriptionally activated by several factors although its stimulation by transforming growth factor ? (TGF-?) has attracted considerable attention. CTGF acts to promote fibroblast proliferation, migration, adhesion, and extracellular matrix formation, and its overproduction

Essam El-Din A. Moussad; David R. Brigstock

2000-01-01

246

Fibroblast Growth Factors Are Required for Efficient Tumor Angiogenesis1  

Microsoft Academic Search

Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF re- ceptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and

Amelia Compagni; Petra Wilgenbus; Maria-Antonietta Impagnatiello; Matt Cotten; Gerhard Christofori

247

The role of the tetraspanin CD151 in primary keratinocyte and fibroblast functions: Implications for wound healing  

SciTech Connect

Previous studies showed that CD151-null mice have a skin wound healing deficit. To gain an understanding of the role of CD151 in re-epithelialisation and dermal contraction, keratinocyte and fibroblast functions were assayed. Primary CD151-null keratinocytes displayed defective migration on Matrigel (a basement membrane equivalent) and laminin-332, the primary adhesion component of basement membranes, but not on collagen-I. Adhesion, spreading and proliferation were also deficient on laminin-332, but not collagen-I. The data suggest that loss of CD151 impairs the function of its primary interaction partners, integrin {alpha}3{beta}1- and/or {alpha}6{beta}4 which bind to laminin-332. Skin fibroblasts also produce CD151 mRNA. CD151-null fibroblasts migrated significantly faster on collagen I than wild type fibroblasts, confirming that they possess functional collagen receptors. However, no significant decrease in the ability of CD151-null fibroblasts to cause contraction in floating collagen gel assays in response to transforming growth factor beta-1 (TGF-{beta}1) or platelet derived growth factor (PDGF-BB) was observed, nor was there an effect on fibroblast adhesion or proliferation on collagen-I. The data implicate CD151 as a facilitator of laminin-332-mediated keratinocyte functions that impact on the re-epithelialisation process intrinsic to wound healing and further suggest a potential novel role for CD151 in fibroblast migration.

Geary, Sean M. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia); Cowin, Allison J. [Child Health Research Institute, North Adelaide, South Australia (Australia); Department of Paediatrics, University of Adelaide, South Australia (Australia); Copeland, Ben; Baleato, Rosa M. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia); Miyazaki, Kaoru [Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Yokohama (Japan); Ashman, Leonie K. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia)], E-mail: leonie.ashman@newcastle.edu.au

2008-07-01

248

The role of vascular endothelial growth factors and fibroblast growth factors in angiogenesis during otitis media.  

PubMed

The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention. PMID:22104377

Husseman, Jacob; Palacios, Sean D; Rivkin, Alexander Z; Oehl, Heinz; Ryan, Allen F

2012-01-01

249

Fibroblast Growth Factor Control of Cartilage Homeostasis  

PubMed Central

Osteoarthritis (OA) and degenerative disc disease (DDD) are similar diseases involving the breakdown of cartilage tissue, and a better understanding of the underlying biochemical processes involved in cartilage degeneration may allow for the development of novel biologic therapies aimed at slowing the disease process. Three members of the fibroblast growth factor (FGF) family, FGF-2, FGF-18, and FGF-8, have been implicated as contributing factors in cartilage homeostasis. The role of FGF-2 is controversial in both articular and intervertebral disc (IVD) cartilage as it has been associated with species- and age-dependent anabolic or catabolic events. Recent evidence suggests that FGF-2 selectively activates FGF receptor 1 (FGFR1) to exert catabolic effects in human articular chondrocytes and IVD tissue via upregulation of matrix-degrading enzyme production, inhibition of extracellular matrix (ECM) accumulation and proteoglycan synthesis, and clustering of cells characteristic of arthritic states. FGF-18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating the FGFR3 pathway, inducing ECM formation and chondrogenic cell differentiation, and inhibiting cell proliferation. These changes result in dispersed chondrocytes or disc cells surrounded by abundant matrix. The role of FGF-8 has recently been identified as a catabolic mediator in rat and rabbit articular cartilage, but its precise biological impact on human adult articular cartilage or IVD tissue remains unknown. The available evidence reveals the promise of FGF-2/FGFR1 antagonists, FGF-18/FGFR3 agonists, and FGF-8 antagonists (i.e., anti-FGF-8 antibody) as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future. PMID:23060229

Ellman, M.B.; Yan, D.; Ahmadinia, K.; Chen, D.; An, H.S.; Im, H.J.

2013-01-01

250

Differences in collagen production between normal and keloid-derived fibroblasts in serum-media co-culture with keloid-derived keratinocytes.  

PubMed

Keloids are characterized by the deposition of excessive extracellular-matrix collagen by abnormal fibroblasts in response to cutaneous injury. Studies to date have largely concentrated on the role of the keloid fibroblast in the pathogenesis of this lesion. Recent studies have highlighted the important concept of epithelial-mesenchymal interactions in normal skin biology. Extrapolating this to keloids in two recent serum-free in vitro studies, we demonstrated increased growth and proliferation, as well as induction of keloid-like collagen secretory characteristics in normal fibroblasts co-cultured with keloid-derived keratinocytes. Most fibroblast culture work to date has been performed in nutrient and growth factor-rich serum media. To investigate how a serum co-culture system might influence epithelial-mesenchymal interactions, [3H] proline incorporation was examined in normal and keloid fibroblasts co-cultured in serum with keratinocytes derived either from normal skin or keloid tissue. Results showed increased [3H] proline incorporation when normal fibroblasts were co-cultured with keloid keratinocytes, which was significantly increased when keloid fibroblasts were co-cultured with keloid keratinocytes. Taken with previous results, this study demonstrates a good correlation between both serum and serum-free co-culture systems, and supports the significance of epithelial-mesenchymal interactions in keloid pathogenesis. PMID:12007718

Phan, Toan-Thang; Lim, Ivor J; Bay, Boon-Huat; Qi, Robert; Huynh, Hung T; Lee, Seng-Teik; Longaker, Michael T

2002-05-01

251

Keratinocytes propagated in serum-free, feeder-free culture conditions fail to form stratified epidermis in a reconstituted skin model.  

PubMed

Primary human epidermal stem cells isolated from skin tissues and subsequently expanded in tissue culture are used for human therapeutic use to reconstitute skin on patients and to generate artificial skin in culture for academic and commercial research. Classically, epidermal cells, known as keratinocytes, required fibroblast feeder support and serum-containing media for serial propagation. In alignment with global efforts to remove potential animal contaminants, many serum-free, feeder-free culture methods have been developed that support derivation and growth of these cells in 2-dimensional culture. Here we show that keratinocytes grown continually in serum-free and feeder-free conditions were unable to form into a stratified, mature epidermis in a skin equivalent model. This is not due to loss of cell potential as keratinocytes propagated in serum-free, feeder-free conditions retain their ability to form stratified epidermis when re-introduced to classic serum-containing media. Extracellular calcium supplementation failed to improve epidermis development. In contrast, the addition of serum to commercial, growth media developed for serum-free expansion of keratinocytes facilitated 3-dimensional stratification in our skin equivalent model. Moreover, the addition of heat-inactivated serum improved the epidermis structure and thickness, suggesting that serum contains factors that both aid and inhibit stratification. PMID:23326335

Lamb, Rebecca; Ambler, Carrie A

2013-01-01

252

Light and electron microscopic immunohistochemical observations of p75 nerve growth factor receptor-immunoreactive dermal nerves in prurigo nodularis  

Microsoft Academic Search

\\u000a Abstract Prurigo nodularis is an inflammatory skin disease characterized by neurohyperplasia. Neurotrophins and their receptors play\\u000a a critical role in nerve growth, differentiation, maturation and maintenance, including cutaneous nerve fiber growth and innervation.\\u000a They may also be responsible for events related to the growth and differentiation control of keratinocytes. To explore the\\u000a exact distribution of the p75 low-affinity nerve growth

Yong Liang; Jan A. Marcusson; Olle Johansson

1999-01-01

253

Angiogenic growth factor expression in benign and malignant vascular tumours.  

PubMed

Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets. Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays. Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p=0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p=0.07) and inflammatory vascular lesions (p=0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p=0.001, p=0.001, p<0.001 and p<0.001 respectively). Notch1 also correlated with Tie2 expression (p=0.004). In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK. PMID:24984271

Young, Robin J; Fernando, Malee; Hughes, David; Brown, Nicola J; Woll, Penella J

2014-08-01

254

[Epidermal growth factor, innovation and safety.  

PubMed

Bioidentical recombinant human epidermal growth factor (rhEGF) is available in concentrations and purity suitable for therapeutic use in long time stable formulations. Beneficial effects in several skin pathologies and lesions have been reported (traumatic and surgical wound healing, laser induced wounds, abnormal scars, keloids, radiation or chemotherapy induced dermatitis, post inflammatory hyperpigmentation or for skin aging damage repairing) and also may be considered for the treatment of several oropharingeal and high gastroesophageal tract mucosa diseases (mouth sores, pharyngeal fistulas, ulcers), and several corneal or conjunctive mucosa lesions. rhEGF has not shown any important side or collateral effects in humans or in laboratory experimentation animals, showing optimal tolerability and safety with continuous use for months. Compounding gives advantages of versatility, individualization, personalization, molecular stability, safety and effectiveness in ideal conditions, showing good tissue penetration, both on intact skin and skin lesions that expose the lower planes to the surface. rhEGF compounds can be considered for prevention or as a treatment of diverse skin and mucosa diseases and conditions through compounding preparations. PMID:25433777

Esquirol Caussa, Jordi; Herrero Vila, Elisabeth

2014-11-26

255

Growth factor synergism and antagonism in early neural crest development.  

PubMed

This review article focuses on data that reveal the importance of synergistic and antagonistic effects in growth factor action during the early phases of neural crest development. Growth factors act in concert in different cell lineages and in several aspects of neural crest cell development, including survival, proliferation, and differentiation. Stem cell factor (SCF) is a survival factor for the neural crest stem cell. Its action is neutralized by neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) through apoptotic cell death. In contrast, SCF alone does not support the survival of melanogenic cells (pigment cell precursors). They require the additional presence of a neurotrophin (NGF, BDNF, or NT-3). Fibroblast growth factor-2 (FGF-2) is an important promoter of proliferation in neuronal progenitor cells. In neural crest cells, fibroblast growth factor treatment alone does not lead to cell expansion but also requires the presence of a neurotrophin. The proliferative stimulus of the fibroblast growth factor - neurotrophin combination is antagonized by transforming growth factor beta-1 (TGFbeta-1). Moreover, TGFbeta-1 promotes the concomitant expression of neuronal markers from two cell lineages, sympathetic neurons and primary sensory neurons, indicating that it acts on a pluripotent neuronal progenitor cell. Moreover, the combination of FGF-2 and NT3, but not other neurotrophins, promotes expression or activation of one of the earliest markers expressed by presumptive sympathetic neuroblasts, the norepinephrine transporter. Taken together, these data emphasize the importance of the concerted action of growth factors in neural crest development at different levels and in several cell lineages. The underlying mechanisms involve growth-factor-induced dependence of the cells on other factors and susceptibility to growth-factor-mediated apoptosis. PMID:10392715

Sieber-Blum, M

1998-01-01

256

20-Hydroxycholecalciferol, Product of Vitamin D3 Hydroxylation by P450scc, Decreases NF-?B Activity by Increasing I?B? Levels in Human Keratinocytes  

Microsoft Academic Search

The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc (CYP11A1) to form 20-hydroxycholecalciferol, which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes. Since nuclear factor-?B (NF-?B) plays a pivotal role in the regulation of cell proliferation, differentiation and apoptosis, we examined the capability of 20-hydroxycholecalciferol to modulate the activity

Zorica Janjetovic; Michal A. Zmijewski; Robert C. Tuckey; Damon A. DeLeon; Minh N. Nguyen; Lawrence M. Pfeffer; Andrzej T. Slominski

2009-01-01

257

Distinct Role of Fibroblast Growth Factor-2 and Vascular Endothelial Growth Factor on Tumor Growth and Angiogenesis  

PubMed Central

Tumors express more than a single angiogenic growth factor. To investigate the relative impact of fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) on tumor growth and neovascularization, we generated tumor cell transfectants differing for VEGF and/or FGF-2 expression. Human endometrial adenocarcinoma HEC-1-B-derived Tet-FGF-2 cells that express FGF-2 under the control of the tetracycline-responsive promoter (Tet-off system) were further transfected with a VEGF121 anti-sense (AS-VEGF) cDNA. Next, Tet-FGF-2 and AS-VEGF/Tet-FGF-2 cells were transplanted subcutaneously in nude mice that received tetracycline or not in the drinking water. Simultaneous expression of FGF-2 and VEGF in Tet-FGF-2 cells resulted in fast-growing lesions characterized by high blood vessel density, patency and permeability, and limited necrosis. Blood vessels were highly heterogeneous in size and frequently associated with pericytes. Inhibition of FGF-2 production by tetracycline caused a significant decrease in tumor burden paralleled by a decrease in blood vessel density and size. AS-VEGF expression resulted in a similar reduction in blood vessel density associated with a significant decrease in pericyte organization, vascular patency, and permeability. The consequent decrease in tumor burden was paralleled by increased tumor hypoxia and necrosis. A limited additional inhibitory effect was exerted by simultaneous down-regulation of FGF-2 and VEGF expression. These findings demonstrate that FGF-2 and VEGF stimulate vascularization synergistically but with distinctive effects on vessel functionality and tumor survival. Blockade of either one of the two growth factors results in a decrease in blood vessel density and, consequently, in tumor burden. However, inhibition of the expression of VEGF, but not of FGF-2, affects also vessel maturation and functionality, leading to tumor hypoxia and necrosis. Our experimental model represents an unique tool to investigate anti-neoplastic therapies in different angiogenic environments. PMID:12759248

Giavazzi, Raffaella; Sennino, Barbara; Coltrini, Daniela; Garofalo, Angela; Dossi, Romina; Ronca, Roberto; Tosatti, Maria Pia Molinari; Presta, Marco

2003-01-01

258

Slow release of ions from internalized silver nanoparticles modifies the epidermal growth factor signaling response.  

PubMed

Due to their distinctive physiochemical properties, including a robust antibacterial activity and plasmonic capability, hundreds of consumer and medical products contain colloidal silver nanoparticles (AgNPs). However, even at sub-toxic dosages, AgNPs are able to disrupt cell functionality, through a yet unknown mechanism. Moreover, internalized AgNPs have the potential to prolong this disruption, even after the removal of excess particles. In the present study, we evaluated the impact, mechanism of action, and continual effects of 50 nm AgNP exposure on epidermal growth factor (EGF) signal transduction within a human keratinocyte (HaCaT) cell line. After AgNP expose, EGF signaling was initially obstructed due to the dissolution of particles into silver ions. However, at longer durations, the internalized AgNPs increased EGF signaling activity. This latter behavior correlated to sustained HaCaT stress, believed to be maintained through the continual dissolution of internalized AgNPs. This study raises concerns that even after exposure ceases, the retained nanomaterials are capable of acting as a slow-release mechanism for metallic ions; continually stressing and modifying normal cellular functionality. PMID:25260222

Comfort, Kristen K; Maurer, Elizabeth I; Hussain, Saber M

2014-11-01

259

Oncogenic human papillomaviruses activate the tumor-associated lens epithelial-derived growth factor (LEDGF) gene.  

PubMed

The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic. PMID:24604027

Leitz, Jenny; Reuschenbach, Miriam; Lohrey, Claudia; Honegger, Anja; Accardi, Rosita; Tommasino, Massimo; Llano, Manuel; von Knebel Doeberitz, Magnus; Hoppe-Seyler, Karin; Hoppe-Seyler, Felix

2014-03-01

260

Oncogenic Human Papillomaviruses Activate the Tumor-Associated Lens Epithelial-Derived Growth Factor (LEDGF) Gene  

PubMed Central

The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic. PMID:24604027

Leitz, Jenny; Reuschenbach, Miriam; Lohrey, Claudia; Honegger, Anja; Accardi, Rosita; Tommasino, Massimo; Llano, Manuel; von Knebel Doeberitz, Magnus; Hoppe-Seyler, Karin; Hoppe-Seyler, Felix

2014-01-01

261

Effect of gamma-hydroxybutyrate on keratinocytes proliferation: A preliminary prospective controlled study in severe burn patients  

PubMed Central

Background: Hypermetabolism and hyposomatotropism related to severe burns lead to impaired wound healing. Growth hormone (GH) boosts wound healing notably following stimulation of the production of insulin-like growth factor-1 (IGF1), a mitogen factor for keratinocytes. Gamma-hydroxybutyrate (GHB) stimulates endogenous GH secretion. Aim: To assess effects of GHB sedation on keratinocytes proliferation (based on immunohistochemical techniques). Design: Monocentric, prospective, controlled trial. Materials and Methods: Patients (aging 18-65 years, burn surface area >30%, expected to be sedated for at least one month) were alternately allocated, at the 5th day following injury, in three groups according to the intravenous GHB dose administered for 21 days: Evening bolus of 50 mg/kg (Group B), continuous infusion at the rate of 10 mg/kg/h (Group C), or absence of GHB (Group P). They all received local standard cares. Immunohistochemistry (Ki67/MIB-1, Ulex europaeus agglutinin-1 and Mac 387 antibodies) was performed at D21 on adjacent unburned skin sample for assessing any keratinocyte activation. Serum IGF1 levels were measured at initiation and completion of the protocol. Statistical Analysis: Categorical variables were compared with Chi-square test. Comparisons of medians were made using Kruskal-Wallis test. Post hoc analyses were performed using Mann-Whitney test with Bonferroni correction for multiple comparisons. A P < 0.05 was considered to be statistically significant. Results: A total of 14 patients completed the study (Group B: n = 5, Group C: n = 5, Group P: n = 4). Continuous administration of GHB was associated with a significant higher Ki67 immunolabeling at D21 (P = 0.049) and with a significant higher increase in the IGF1 concentrations at D21 (P = 0.024). No adverse effects were disclosed. Conclusions: Our preliminary data support a positive effect of GHB on keratinocyte proliferation and are encouraging enough to warrant large prospective studies. PMID:25024938

Rousseau, Anne-Françoise; Bargues, Laurent; Bever, Hervé Le; Vest, Philippe; Cavalier, Etienne; Ledoux, Didier; Piérard, Gérald E.; Damas, Pierre

2014-01-01

262

Factors affecting filamentous growth of Sphaerotilus natans.  

PubMed

Filamentous growth in cultures of Sphaerotilus natans can be measured and compared with total growth by a standardized procedure of winding filaments around an inoculating needle. Filaments and residual growth are then separately washed on Millipore filters, dried, and weighed. This method has been used to study changes in the growth habit of S. natans elicited by changes in the concentration of nutrients in the medium. The concentration of peptone, in a medium containing a sugar, phosphate buffer, and inorganic salts, has a much greater effect on the proportion of filamentous growth than does the nature or concentration of the carbon source or the concentration of phosphate buffer. Filament formation is significantly inhibited by concentrations of peptone greater than 0.25%; further increases in peptone concentration stimulate the production of large amounts of capsular material. Increasing the concentration of phosphate buffer to 0.05 M almost completely inhibits growth of S. natans. PMID:13897283

GAUDY, E; WOLFE, R S

1961-11-01

263

Induction of Hair Growth by Insulin-Like Growth Factor-1 in 1,763 MHz Radiofrequency-Irradiated Hair Follicle Cells  

PubMed Central

Radiofrequency (RF) radiation does not transfer high energy to break the covalent bonds of macromolecules, but these low energy stimuli might be sufficient to induce molecular responses in a specific manner. We monitored the effect of 1,763 MHz RF radiation on cultured human dermal papilla cells (hDPCs) by evaluating changes in the expression of cytokines related to hair growth. The expression of insulin-like growth factor-1 (IGF-1) mRNA in hDPCs was significantly induced upon RF radiation at the specific absorption rate of 10 W/kg, which resulted in increased expression of B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) and cyclin D1 (CCND1) proteins and increased phosphorylation of MAPK1 protein. Exposure to 10 W/kg RF radiation 1 h per day for 7 days significantly enhanced hair shaft elongation in ex vivo hair organ cultures. In RF-exposed follicular matrix keratinocytes in the hair bulb, the expression of Ki-67 was increased, while the signal for terminal deoxynucleotidyl transferase dUTP nick end labeling was reduced. From these results, we suggest that 1,763 MHz RF exposure stimulates hair growth in vitro through the induction of IGF-1 in hDPCs. PMID:22164296

Jo, Seong Jin; Cho, A-Ri; Jeon, Soon-Ik; Choi, Hyung-Do; Kim, Kyu Han; Park, Gun-Sik; Pack, Jeong-Ki; Kwon, Oh Sang; Park, Woong-Yang

2011-01-01

264

Green tea polyphenols induce differentiation and proliferation in epidermal keratinocytes.  

PubMed

The most abundant green tea polyphenol, epigallocatechin-3-gallate (EGCG), was found to induce differential effects between tumor cells and normal cells. Nevertheless, how normal epithelial cells respond to the polyphenol at concentrations for which tumor cells undergo apoptosis is undefined. The current study tested exponentially growing and aged primary human epidermal keratinocytes in response to EGCG or a mixture of the four major green tea polyphenols. EGCG elicited cell differentiation with associated induction of p57/KIP2 within 24 h in growing keratinocytes, measured by the expression of keratin 1, filaggrin, and transglutaminase activity. Aged keratinocytes, which exhibited low basal cellular activities after culturing in growth medium for up to 25 days, renewed DNA synthesis and activated succinate dehydrogenase up to 37-fold upon exposure to either EGCG or the polyphenols. These results suggest that tea polyphenols may be used for treatment of wounds or certain skin conditions characterized by altered cellular activities or metabolism. PMID:12663686

Hsu, Stephen; Bollag, Wendy B; Lewis, Jill; Huang, Qin; Singh, Baldev; Sharawy, Mohamed; Yamamoto, Tetsuya; Schuster, George

2003-07-01

265

Growth factors are released by mechanically wounded endothelial cells  

Microsoft Academic Search

Growth factors may be required at sites of mechanical injury and normal wear and tear in vivo, suggesting that the direct action of mechanical forces on cells could lead to growth factor release. Scraping of cells from the tissue culture substratum at 37°C was used to test this possibility. We show that scraping closely mimics in vitro both the transient

Paul L. McNeil; Lakshmi Muthukrishnan; Elizabeth Warder; Patricia A. D

1989-01-01

266

Nanoparticle mediated controlled delivery of dual growth factors.  

PubMed

Peripheral nerve functional recovery after nerve injury generally requires multiple growth factors by synergistic effect. However, the optical combination of multiple synergistic growth factors for axonal regeneration has been scarcely considered up to now. Meanwhile, the use of growth factors in promoting nerve regeneration was limited by its short biological half-life in vivo, its vulnerability to structure disruption or hydrolyzation, leading to loss of bioactivity. Herein, a novel polymeric nanoparticle delivery system composed of heparin and ?-poly-L-lysine (PL) was prepared for control release of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF). The nanoparticles were synthesized by polyelectrolyte complexation in aqueous solution at room temperature, followed by cross-linking with biological genipin. The obtained nanoparticles had a spherical shape, with a mean diameter of about 246 nm, and high growth factors encapsulation efficiency as well as good stability. NGF and bFGF were encapsulated in the nanoparticles and showed a continuous and slow release behavior in vitro. The bioactivities of the released growth factors were evaluated, and exhibited the synergistic effect. The controlled release of the dual synergistic growth factors would improve the treatment of peripheral nerve injury to mimic the natural cellular microenvironments. PMID:24430559

Zhang, LuZhong; Zhou, YouLang; Li, GuiCai; Zhao, YaHong; Gu, XiaoSong; Yang, YuMin

2014-02-01

267

Functional upregulation of system xc? by fibroblast growth factor-2  

Microsoft Academic Search

The cystine\\/glutamate antiporter (system xc?) is a Na+-independent amino acid transport system. Disruption of this system may lead to multiple effects in the CNS including decreased cellular glutathione. Since multiple neurological diseases involve glutathione depletion, and disruption of growth factor signaling has also been implicated in these diseases, it is possible that some growth factors effects are mediated by regulation

XiaoQian Liu; Jon Resch; Travis Rush; Doug Lobner

268

Extracellular matrix and growth factors in branching morphogenesis  

NASA Technical Reports Server (NTRS)

The unifying hypothesis of the NSCORT in gravitational biology postulates that the ECM and growth factors are key interrelated components of a macromolecular regulatory system. The ECM is known to be important in growth and branching morphogenesis of embryonic organs. Growth factors have been detected in the developing embryo, and often the pattern of localization is associated with areas undergoing epithelial-mesenchymal interactions. Causal relationships between these components may be of fundamental importance in control of branching morphogenesis.

Hardman, P.; Spooner, B. S.

1993-01-01

269

Importance of Transforming Growth Factor a\\/Epidermal Growth Factor Receptor Autocrine Growth Mechanism in an Ovarian Cancer Cell Line in Vivo  

Microsoft Academic Search

We have elucidated the importance of a transforming growth factor (TGF) a and epidermal growth factor receptor autocrine mechanism on the growth of a human ovarian serous cystadenocarcinoma-derived cell line (SHIN-3) in vitro. In this study, westudied the biological significance of this autocrine mechanism in vivo using female athymic nude (nu\\/nu) mice. We measured the mouse plasma epidermal growth factor

Hirohisa Kurachi; Ken-ichiro Morishige; Kyoka Amemiya; Hiroshi Adachi; Kenji Hirota; Akira Miyake; Osamu Tanizawa; Yasuhiko Sakoyama

1991-01-01

270

Topical application of 5-fluorouracil on attic cholesteatoma results in downregulation of keratinocyte growth factor and reduction of proliferative activity  

Microsoft Academic Search

To investigate the cell-biological effect of topically applied 5-fluorouracil (5-FU) on middle ear cholesteatoma, 12 attic\\u000a cholesteatomas were treated with topical application of 5-FU cream, two to five times with an interval of 2 weeks (5-FU group).\\u000a The control group comprised 65 cholesteatoma that were not treated with 5-FU. All lesions were later excised surgically and\\u000a processed for immunohistochemical analyses of

Tomomi Yamamoto-Fukuda; Mariko Terakado; Yoshitaka Hishikawa; Takehiko Koji; Haruo Takahashi

2008-01-01

271

Vascular endothelial growth factor and vascular endothelial growth factor receptor-2 expression in mdx mouse brain.  

PubMed

Recent data have demonstrated that vascular endothelial growth factor (VEGF) is expressed by subsets of neurons, coincident with angiogenesis within its developing cerebral cortex. In this study, with the aim of elucidating the mechanisms of vascular involvement during brain impairment in Duchenne muscular distrophy (DMD), we have correlated the vascular density with VEGF and VEGF receptor-2 (VEGFR-2) expression in the brain cortex of normal and mdx mouse, an animal model with a genetic defect in a region homologous with the human DMD gene. Results showed that in mdx mouse, tissue area occupied by microvessels positive to factor VIII related antigen and VEGFR-2 increased in parallel to the tissue area occupied by neurons positive to VEGF. Our data suggest that increased vascularity in the brain of mdx mouse may be due, at least in part, to proliferation of endothelial cells in response to VEGF secreted by neuronal cells. PMID:12384233

Nico, Beatrice; Corsi, Patrizia; Vacca, Angelo; Roncali, Luisa; Ribatti, Domenico

2002-10-25

272

Identification of functional SNPs potentially served as a genetic risk factor for the pathogenesis of parakeratosis in the gene encoding human deoxyribonuclease I-like 2 (DNase 1L2) implicated in terminal differentiation of keratinocytes.  

PubMed

In the present study, we evaluated all of the 35 non-synonymous SNPs in the gene encoding DNase I-like 2 (DNase 1L2), implicated in terminal differentiation of keratinocytes, to seek a functional SNP that would potentially affect the levels of in vivo DNase 1L2 activity. Based on a compiled expression analysis of the amino acid-substituted DNase 1L2 corresponding to each of the 35 non-synonymous SNPs in the gene, these 35 SNPs were grouped into 4 classes according to the alteration of catalytic activity caused by the corresponding amino acid substitution in the DNase 1L2 protein; we were able to identify 12 non-synonymous SNPs as functional SNPs abolishing or substantially reducing the activity. Almost all of the amino acid residues corresponding to the SNPs abolishing the activity were completely or highly conserved in not only the DNase I family, but also animal DNase 1L2. Each of the minor alleles of these functional SNPs producing a loss-of-function or low activity-harboring variant was absent in 14 different populations derived from 3 ethnic groups, allowing us to assume that DNASE1L2 is generally well conserved with regard to these non-synonymous SNPs, thereby avoiding any marked reduction of the enzyme activity in human populations. However, it seems likely that each of the minor alleles for these SNPs may serve as a genetic risk factor for multiple skin diseases such as psoriasis, in which there is an aberrant retention of nuclear chromatin in cornified keratinocytes through incomplete DNA degradation. PMID:25576224

Ueki, Misuzu; Takeshita, Haruo; Kimura-Kataoka, Kaori; Fujihara, Junko; Iida, Reiko; Yasuda, Toshihiro

2015-04-25

273

Factors contributing to posttraumatic growth: a proposed structural equation model.  

PubMed

With the current shift to include positive outcomes of trauma, this research was designed to explore factors that allow growth to occur. Structural equation modeling was used to test a model for understanding posttraumatic growth. A sample (N = 174) of bereaved HIV/AIDS caregivers completed questionnaires. Spirituality, social support, and stressors were found to have a positive relationship with growth. Facilitation of posttraumatic growth is crucial to all helping professions. PMID:12921208

Cadell, Susan; Regehr, Cheryl; Hemsworth, David

2003-07-01

274

TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)  

EPA Science Inventory

TITLE: TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox ...

275

Endogenous versus Exogenous Growth Factor Regulation of Articular Chondrocytes  

PubMed Central

Anabolic growth factors that regulate the function of articular chondrocytes are candidates for articular cartilage repair. Such factors may be delivered by pharmacotherapy in the form of exogenous proteins, or by gene therapy as endogenous proteins. It is unknown whether delivery method influences growth factor effectiveness in regulating articular chondrocyte reparative functions. We treated adult bovine articular chondrocytes with exogenous recombinant insulin-like growth factor-I (IGF-I) and transforming growth factor-beta1 (TGF-?1), or with the genes encoding these growth factors for endogenous production. Treatment effects were measured as change in chondrocyte DNA content, glycosaminoglycan production, and aggrecan gene expression. We found that IGF-I stimulated chondrocyte biosynthesis similarly when delivered by either exogenous or endogenous means. In contrast, exogenous TGF-ß1 stimulated these reparative functions, while endogenous TGF-ß1 had little effect. Endogenous TGF-ß1 became more bioactive following activation of the transgene protein product. These data indicate that effective mechanisms of growth factor delivery for articular cartilage repair may differ for different growth factors. In the case of IGF-I, gene therapy or protein therapy appear to be viable options. In contrast, TGF-ß1 gene therapy may be constrained by a limited ability of chondrocytes to convert latent complexes to an active form. PMID:24105960

Shi, Shuiliang; Chan, Albert G.; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.

2014-01-01

276

Targeting the opioid growth factor: opioid growth factor receptor axis for treatment of human ovarian cancer.  

PubMed

The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a biological pathway that is present in human ovarian cancer cells and tissues. OGF, chemically termed [Met(5)]-enkephalin, is an endogenous opioid peptide that interfaces with OGFr to delay cells moving through the cell cycle by upregulation of cyclin-dependent inhibitory kinase pathways. OGF inhibitory activity is dose dependent, receptor mediated, reversible, protein and RNA dependent, but not related to apoptosis or necrosis. The OGF-OGFr axis can be targeted for treatment of human ovarian cancer by (i) administration of exogenous OGF, (ii) genetic manipulation to over-express OGFr and (iii) use of low dosages of naltrexone, an opioid antagonist, which stimulates production of OGF and OGFr for subsequent interaction following blockade of the receptor. The OGF-OGFr axis may be a feasible target for treatment of cancer of the ovary (i) in a prophylactic fashion, (ii) following cytoreduction or (iii) in conjunction with standard chemotherapy for additive effectiveness. In summary, preclinical data support the transition of these novel therapies for treatment of human ovarian cancer from the bench to bedside to provide additional targets for treatment of this devastating disease. PMID:23856908

Zagon, Ian S; Donahue, Renee; McLaughlin, Patricia J

2013-05-01

277

Growth factor regulation of neutrophil-endothelial cell interactions  

Microsoft Academic Search

The effects of the angiogenic factors basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on human poly- morphonuclear leukocyte (PMNL)-endothelial cell adhesion and transendothelial migration (TEM) were investigated. Stimulation of human umbilical vein endothelial cells by VEGF or bFGF for 18 h up-regulated intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 expression and significantly increased

Hong Zhang; Andrew C. Issekutz

2001-01-01

278

Upregulation of oxidant-induced VEGF expression in cultured keratinocytes by a grape seed proanthocyanidin extract.  

PubMed

Angiogenesis plays a central role in wound healing. Among many known growth factors, vascular endothelial growth factor (VEGF) is believed to be the most prevalent, efficacious, and long-term signal that is known to stimulate angiogenesis in wounds. The wound site is rich in oxidants such as hydrogen peroxide mostly contributed by neutrophils and macrophages. Proanthocyanidins or condensed tannins are a group of biologically active polyphenolic bioflavonoids that are synthesized by many plants. This study provides first evidence showing that natural extracts such as grape seed proanthocyanidin extract containing 5000 ppm resveratrol (GSPE) facilitates oxidant-induced VEGF expression in keratinocytes. Using a ribonuclease protection assay (RPA), the ability of GSPE to regulate oxidant-induced changes in several angiogenesis-related genes were studied. While mRNA responses were studied using RPA, VEGF protein release from cells to the culture medium was studied using ELISA. Pretreatment of HaCaT keratinocytes with GSPE upregulated both hydrogen peroxide as well as TNF-alpha-induced VEGF expression and release. The current results suggest that GSPE may have beneficial therapeutic effects in promoting dermal wound healing and other related skin disorders. PMID:11425488

Khanna, S; Roy, S; Bagchi, D; Bagchi, M; Sen, C K

2001-07-01

279

A Complex Growth Factor in Duodenal Tissue  

Microsoft Academic Search

A commercial preparation of dry duodenal tissue was hydrolyzed and fractionated to determine whether this material contained thyroid hormones. Five fractions, capable of reinstating growth of growth-arrested, sulfaguanidine-fed rats, were obtained. All were stable to acid hydrolysis and insoluble in 0.1 N HC1. They differed from each other with respect to their solubility in benzene, acetone and methanol, and their

C. J. ACKERMAN

280

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer  

Microsoft Academic Search

Solid tumors must induce a vascular stroma to grow beyond a minimal size, and the intensity of the angiogenic response has been correlated with prognosis in breast cancer patients. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a secreted protein that has been implicated in tumor-associated angiogenesis. Vascular permeability factor directly stimulates endothelial cell growth

Lawrence F Brown; Brygida Berse; Robert W Jackman; Kathi Tognazzi; Anthony J Guidi; Harold F Dvorak; Donald R Senger; James L Connolly; Stuart J Schnitt

1995-01-01

281

S100A8/A9 Stimulates Keratinocyte Proliferation in the Development of Squamous Cell Carcinoma of the Skin via the Receptor for Advanced Glycation-End Products  

PubMed Central

Squamous cell carcinoma (SCC) is the most common neoplasm in organ transplant recipients (OTR) on long-term immunosuppression and occurs 60- to 100-fold more frequently than in the general population. Here, we present the receptor for advanced glycation end products (RAGE) and S100A8/A9 as important factors driving normal and tumor keratinocyte proliferation. RAGE and S100A8/A9 were transcriptionally upregulated in SCC compared to normal epidermis, as well as in OTR compared to immunocompetent patients (IC) with SCC. The proliferation of normal and SCC keratinocytes was induced by exposure to exogenous S100A8/A9 which in turn was abolished by blocking of RAGE. The migratory activities of normal and SCC keratinocytes were also increased upon exposure to S100A8/A9. We demonstrated that exogenous S100A8/A9 induces phosphorylation of p38 and SAPK/JNK followed by activation of ERK1/2. We hypothesize that RAGE and S100A8/A9 contribute to the development of human SCC by modulating keratinocyte growth and migration. These processes do not seem to be impaired by profound drug-mediated immunosuppression in OTR. PMID:25811984

Iotzova-Weiss, Guergana; Dziunycz, Piotr J.; Freiberger, Sandra N.; Läuchli, Severin; Hafner, Jürg; Vogl, Thomas; French, Lars E.; Hofbauer, Günther F. L.

2015-01-01

282

Regulation of transferrin receptor expression at the cell surface by insulin-like growth factors, epidermal growth factor and platelet-derived growth factor  

SciTech Connect

Addition of platelet-derived growth factor (PDGF), recombinant insulin-like growth factor I (rIGF-I) or epidermal growth factor (EGF) to BALB/c 3T3 fibroblasts causes a marked increase in the binding of (/sup 125/I) diferric transferrin to cell surface receptors. This effect is very rapid and is complete within 5 minutes. The effect is transient with (/sup 125/I) diferric transferrin binding returning to control values within 25 minutes. In contrast, PDGF and rIGF-I cause a prolonged stimulation of (/sup 125/I) diferric transferrin binding that could be observed up to 2 hours. The increase in the binding of (/sup 125/I) diferric transferrin caused by growth factors was investigated by analysis of the binding isotherm. EGF, PDGF and rIGF-I were found to increase the cell surface expression of transferrin receptors rather than to alter the affinity of the transferrin receptors. Furthermore, PDGF and rIGF-I stimulated the sustained uptake of (/sup 59/Fe) diferric transferrin by BALB/c 3T3 fibroblasts. Thus, the effect of these growth factors to increase the cell surface expression of the transferrin receptor appears to have an important physiological consequence.

Davis, R.J.; Kuck, L.; Faucher, M.; Czech, M.P.

1986-05-01

283

Nerve conduits and growth factor delivery in peripheral nerve repair.  

PubMed

Peripheral nerves possess the capacity of self-regeneration after traumatic injury. Transected peripheral nerves can be bridged by direct surgical coaptation of the two nerve stumps or by interposing autografts or biological (veins) or synthetic nerve conduits (NC). NC are tubular structures that guide the regenerating axons to the distal nerve stump. Early synthetic NC have primarily been made of silicone because of the relative flexibility and biocompatibility of this material and because medical-grade silicone tubes were readily available in various dimensions. Nowadays, NC are preferably made of biodegradable materials such as collagen, aliphatic polyesters, or polyurethanes. Although NC assist in guiding regenerating nerves, satisfactory functional restoration of severed nerves may further require exogenous growth factors. Therefore, authors have proposed NC with integrated delivery systems for growth factors or growth factor-producing cells. This article reviews the most important designs of NC with integrated delivery systems for localized release of growth factors. The various systems discussed comprise NC with growth factors being released from various types of matrices, from transplanted cells (Schwann cells or mesenchymal stem cells), or through genetic modification of cells naturally present at the site of injured tissue. Acellular delivery systems for growth factors include the NC wall itself, biodegradable microspheres seeded onto the internal surface of the NC wall, or matrices that are filled into the lumen of the NC and immobilize the growth factors through physical-chemical interactions or specific ligand-receptor interactions. A very promising and elegant system appears to be longitudinally aligned fibers inserted in the lumen of a NC that deliver the growth factors and provide additional guidance for Schwann cells and axons. This review also attempts to appreciate the most promising approaches and emphasize the importance of growth factor delivery kinetics. PMID:17565531

Pfister, Lukas A; Papaloïzos, Michaël; Merkle, Hans P; Gander, Bruno

2007-06-01

284

Transgenic Studies with a Keratin Promoter-Driven Growth Hormone Transgene: Prospects for Gene Therapy  

NASA Astrophysics Data System (ADS)

Keratinocytes are potentially appealing vehicles for the delivery of secreted gene products because they can be transferred to human skin by the relatively simple procedure of grafting. Adult human keratinocytes can be efficiently propagated in culture with sufficient proliferative capacity to produce enough epidermis to cover the body surface of an average adult. However, the feasibility of delivering secreted proteins through skin grafting rests upon (i) the strength of the promoter in keratinocytes and (ii) the efficiency of protein transport through the basement membrane of the stratified epithelium and into the bloodstream. In this paper, we use transgenic technology to demonstrate that the activity of the human keratin 14 promoter remains high in adult skin and that keratinocyte-derived human growth hormone (hGH) can be produced, secreted, and transported to the bloodstream of mice with efficiency that is sufficient to exceed by an order of magnitude the circulating hGH concentration in growing children. Transgenic skin grafts from these adults continue to produce and secrete hGH stably, at ? 1/10 physiological levels in the bloodstream of nontransgenic recipient mice. These studies underscore the utility of the keratin 14 promoter for expressing foreign transgenes in keratinocytes and demonstrate that keratinocytes can be used as effective vehicles for transporting factors to the bloodstream and for eliciting metabolic changes. These findings have important implications for considering the keratinocyte as a possible vehicle for gene therapy.

Wang, Xiaoming; Zinkel, Sandra; Polonsky, Kenneth; Fuchs, Elaine

1997-01-01

285

Platelet-rich growth factor in oral and maxillofacial surgery  

PubMed Central

Platelet-rich growth factor is an innovative regenerative therapy used to promote hard and soft tissue healing. It involves the application of autologous platelet-leukocyte-rich plasma containing growth factors and thrombin directly to the site of treatment. It is the intrinsic growth factors released by activated platelets which are concentrated in a topical gel formula. Clinically, it is an affordable treatment with potentially broad spectrum of applications in maxillofacial surgery especially in the treatment of complex or refractory wounds. The present article reviews its various applications not only in the specialization of oral and maxillofacial surgery but also in regenerative medicine. PMID:23833484

Pal, Uma Shanker; Mohammad, Shadab; Singh, Rakesh K.; Das, Somdipto; Singh, Nimisha; Singh, Mayank

2012-01-01

286

Dual chain synthetic heparin-binding growth factor analogs  

DOEpatents

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Zamora, Paul O. (Gaithersburg, MD); Pena, Louis A. (Poquott, NY); Lin, Xinhua (Plainview, NY)

2009-10-06

287

Dual chain synthetic heparin-binding growth factor analogs  

DOEpatents

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Zamora, Paul O. (Gaithersburg, MD); Pena, Louis A. (Poquott, NY); Lin, Xinhua (Plainview, NY)

2012-04-24

288

Intestinal hormones and growth factors: Effects on the small intestine  

PubMed Central

There are various hormones and growth factors which may modify the intestinal absorption of nutrients, and which might thereby be useful in a therapeutic setting, such as in persons with short bowel syndrome. In partI, we focus first on insulin-like growth factors, epidermal and transferring growth factors, thyroid hormones and glucocorticosteroids. Part II will detail the effects of glucagon-like peptide (GLP)-2 on intestinal absorption and adaptation, and the potential for an additive effect of GLP2 plus steroids. PMID:19152442

Drozdowski, Laurie; Thomson, Alan BR

2009-01-01

289

Material factors influencing metallic whisker growth  

NASA Astrophysics Data System (ADS)

Whiskering refers to the formation of slender, long, metallic filaments, much thinner than a human hair, that grow on a metallic thin film surface. They are readily observed for pure and alloyed zinc (Zn), silver (Ag), cadmium (Cd), indium (In), and tin (Sn) surfaces. The longest reported whisker length is 4.5 mm long but most high-aspect ratio whiskers range from 1-500 mum. The focus of this research is upon Sn whiskers. Sn whiskers pose serious reliability problems for the electronics industry and are known to be the source of failure in a wide range of electronic devices, such as nuclear power facilities, heart pacemakers, commercial satellites, aviation radar, telecommunication equipment, and desktop computers. The problem with whiskering has been recently exacerbated by the worldwide shift to lead (Pb) free electronics and the continuing reduction in electrical contact pitches. A thorough understanding of the growth mechanism of Sn whiskers is urgently needed. Currently, there is no universally accepted model that explains the broad range of observations on whiskering. The goals of this research are: (1) to develop a more detailed understanding of the physical mechanisms leading to the initiation and growth of Sn whiskers and (2) to outline reasonable mitigation strategies that could be followed to reduce or eliminate the problem of Sn whiskers. The major contributions of this work are: (1) A reliable method for growing Sn whiskers with predictable incubation times has been developed and tested. (2) A surface oxide is not necessary for whisker growth. (3) Intermetallic compounds (IMC) are not necessary for whisker growth. (4) Smoother, not rougher, substrate surfaces promote whisker growth. (5) Whiskers grow under both compressive and tensile thin film stress states. (6) Whisker growth increases with externally applied compression and tension forces. (7) Sn whiskers are composed of pure Sn except for the expected thin, native Sn oxide on their surface. (8) For Sn on brass, the atom feedstock for whiskers lies within the film exclusively; the brass substrate does not contribute to whisker production. (9) The volume of film consumed by a metallic whisker is a simple volumetric calculation. (10) There are likely to be multiple mechanisms of whisker growth depending on the substrate - thin film system. (11) In general, the thickness of a metallic film does not have an effect on whisker growth qualities.

Rodekohr, Chad L.

290

Synthesis and physiological activity of heterodimers comprising different splice forms of vascular endothelial growth factor and placenta growth factor.  

PubMed Central

Vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) are members of a dimeric-growth-factor family with angiogenic properties. VEGF is a highly potent and specific mitogen for endothelial cells, playing a vital role in angiogenesis in vivo. The role of PIGF is less clear. We expressed the monomeric splice forms VEGF-165, VEGF-121, PIGF-1 and PIGF-2 as unfused genes in Escherichia coli using the pCYTEXP expression system. In vitro dimerization experiments revealed that both homo- and hetero-dimers can be formed from these monomeric proteins. The dimers were tested for their ability to promote capillary growth in vivo and stimulate DNA synthesis in cultured human vascular endothelial cells. Heterodimers comprising different VEGF splice forms, or combinations of VEGF/PIGF splice forms, showed mitogenic activity. The results demonstrate that four different heterodimeric growth factors are likely to have as yet uncharacterized functions in vivo. PMID:8670141

Birkenhäger, R; Schneppe, B; Röckl, W; Wilting, J; Weich, H A; McCarthy, J E

1996-01-01

291

Original article Insulin-like growth factorI during growth in bulls  

E-print Network

the growth period. An age-dependent increase was also observed for blood levels of insulin, thyroxineOriginal article Insulin-like growth factorI during growth in bulls H. Ronge J. Blum Université de-4-1988, accepted 24-11-1988) Summary ― In 10 bulls, changes in blood plasma concentrations of insulin

Paris-Sud XI, Université de

292

Stimulation of Fibroblast Cell Growth, Matrix Production, and Granulation Tissue Formation by Connective Tissue Growth Factor  

Microsoft Academic Search

Connective tissue growth factor (CTGF) is a 36- to 38-kDa peptide that is selectively induced by transforming growth factor-? (TGF-?) in fibroblastic cell types. We compared the biologic activities of CTGF with TGF-? on fibroblasts in culture and in animal models of fibroplasia. CTGF was active as a mitogen in monolayer cultures of normal rat kidney fibroblasts. CTGF did not

Ken Frazier; Shawn Williams; Devashish Kothapalli; Helene Klapper; Gary R. Grotendorst

1996-01-01

293

Non-thermal Plasma Activates Human Keratinocytes by Stimulation of Antioxidant and Phase II Pathways.  

PubMed

Non-thermal atmospheric pressure plasma provides a novel therapeutic opportunity to control redox-based processes, e.g. wound healing, cancer, and inflammatory diseases. By spatial and time-resolved delivery of reactive oxygen and nitrogen species, it allows stimulation or inhibition of cellular processes in biological systems. Our data show that both gene and protein expression is highly affected by non-thermal plasma. Nuclear factor erythroid-related factor 2 (NRF2) and phase II enzyme pathway components were found to act as key controllers orchestrating the cellular response in keratinocytes. Additionally, glutathione metabolism, which is a marker for NRF2-related signaling events, was affected. Among the most robustly increased genes and proteins, heme oxygenase 1, NADPH-quinone oxidoreductase 1, and growth factors were found. The roles of NRF2 targets, investigated by siRNA silencing, revealed that NRF2 acts as an important switch for sensing oxidative stress events. Moreover, the influence of non-thermal plasma on the NRF2 pathway prepares cells against exogenic noxae and increases their resilience against oxidative species. Via paracrine mechanisms, distant cells benefit from cell-cell communication. The finding that non-thermal plasma triggers hormesis-like processes in keratinocytes facilitates the understanding of plasma-tissue interaction and its clinical application. PMID:25589789

Schmidt, Anke; Dietrich, Stephan; Steuer, Anna; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Masur, Kai; Wende, Kristian

2015-03-13

294

Mechanism of Macrophage-Derived Chemokine/CCL22 Production by HaCaT Keratinocytes  

PubMed Central

Background CC chemokine ligand 17 (CCL17) and CCL22 are the functional ligands for CCR4. We previously reported that inhibitors of nuclear factor-kappa B and p38 mitogen-activated protein kinase (p38 MAPK), but not of extracellular signal-related kinase (ERK), inhibited tumor necrosis factor (TNF)-?- and interferon (IFN)-?-induced production of CCL17 by the human keratinocyte cell line, HaCaT. Further, an inhibitor of epidermal growth factor receptor (EGFR) enhanced the CCL17 production by these keratinocytes. Objective To identify the mechanism underlying CCL22 production by HaCaT cells. Methods We investigated the signal transduction pathways by which TNF-? and IFN-? stimulate HaCaT cells to produce CCL22 by adding various inhibitors. Results TNF-?- and IFN-?-induced CCL22 production was inhibited by PD98059, PD153035, Bay 11-7085, SB202190, c-Jun N-terminal kinase (JNK) inhibitor II, and Janus kinase (JAK) inhibitor 1. Conclusion Our results indicate that CCL22 production in HaCaT cells is dependent on ERK, EGFR, p38 MAPK, JNK, and JAK and is mediated by different signal pathways from those regulating CCL17 production. Altogether, our previous and present results suggest that EGFR activation represses CCL17 but enhances CCL22 production by these cells. PMID:25834353

Yano, Chizuko; Komine, Mayumi; Kagami, Shinji; Tsunemi, Yuichiro; Ohtsuki, Mamitaro; Nakagawa, Hidemi

2015-01-01

295

20-Hydroxycholecalciferol, Product of Vitamin D3 Hydroxylation by P450scc, Decreases NF-?B Activity by Increasing I?B? Levels in Human Keratinocytes  

PubMed Central

The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc (CYP11A1) to form 20-hydroxycholecalciferol, which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes. Since nuclear factor-?B (NF-?B) plays a pivotal role in the regulation of cell proliferation, differentiation and apoptosis, we examined the capability of 20-hydroxycholecalciferol to modulate the activity of NF-?B, using 1,25-dihydroxycholecalciferol (calcitriol) as a positive control. 20-hydroxycholecalciferol inhibits the activation of NF?B DNA binding activity as well as NF-?B-driven reporter gene activity in keratinocytes. Also, 20-hydroxycholecalciferol induced significant increases in the mRNA and protein levels of the NF-?B inhibitor protein, I?B?, in a time dependent manner, while no changes in total NF-?B-p65 mRNA or protein levels were observed. Another measure of NF-?B activity, p65 translocation from the cytoplasm into the nucleus was also inhibited in extracts of 20-hydroxycholecalciferol treated keratinocytes. Increased I?B? was concomitantly observed in cytosolic extracts of 20-hydroxycholecalciferol treated keratinocytes, as determined by immunoblotting and immunofluorescent staining. In keratinocytes lacking vitamin D receptor (VDR), 20-hydroxycholecalciferol did not affect I?B? mRNA levels, indicating that it requires VDR for its action on NF-?B activity. Comparison of the effects of calcitrol, hormonally active form of vitamin D3, with 20-hydrocholecalciferol show that both agents have a similar potency in inhibiting NF-?B. Since NF-?B is a major transcription factor for the induction of inflammatory mediators, our findings indicate that 20-hydroxycholecalciferol may be an effective therapeutic agent for inflammatory and hyperproliferative skin diseases. PMID:19543524

Janjetovic, Zorica; Zmijewski, Michal A.; Tuckey, Robert C.; DeLeon, Damon A.; Nguyen, Minh N.; Pfeffer, Lawrence M.; Slominski, Andrzej T.

2009-01-01

296

Regulation of Transforming Growth Factor ?1, Platelet-Derived Growth Factor, and Basic Fibroblast Growth Factor by Silicone Gel Sheeting in Early-Stage Scarring  

PubMed Central

Background Hypertrophic scars and keloids are associated with abnormal levels of growth factors. Silicone gel sheets are effective in treating and preventing hypertrophic scars and keloids. There has been no report on the change in growth factors in the scar tissue following the use of silicone gel sheeting for scar prevention. A prospective controlled trial was performed to evaluate whether growth factors are altered by the application of a silicone gel sheet on a fresh surgical scar. Methods Four of seven enrolled patients completed the study. Transforming growth factor (TGF)-?1, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) were investigated immunohistochemically in biopsies taken from five scars at 4 months following surgery. Results In both the epidermis and the dermis, the expression of TGF-?1 (P=0.042 and P=0.042) and PDGF (P=0.043 and P=0.042) was significantly lower in the case of silicone gel sheet-treated scars than in the case of untreated scars. The expression of bFGF in the dermis was significantly higher in the case of silicone gel sheet-treated scars than in the case of untreated scars (P=0.042), but in the epidermis, the expression of bFGF showed no significant difference between the groups (P=0.655). Conclusions The levels of TGF-?1, PDGF, and bFGF are altered by the silicone gel sheet treatment, which might be one of the mechanisms of action in scar prevention. PMID:25606485

Choi, Jaehoon; Lee, Eun Hee; Park, Sang Woo

2015-01-01

297

A keratinocyte's course of life.  

PubMed

An adequate permeability barrier function of the mammalian epidermis is guaranteed by the characteristic architecture of the stratum corneum. This uppermost layer consists of a highly organized extracellular lipid compartment which is tightly joined to the corneocytes. The generation of the extracellular lipid compartment and the transformation of the keratinocytes into corneocytes are the main features of epidermal differentiation. However, equally important is the continuous renewal of the stratum corneum, which is insured by a careful balance between the replenishment of new keratinocytes from the proliferating basal layer, and the well-orchestrated loss of the most superficial cells after the so-called 'epidermal programmed cell death'. In this overview, the complete life of keratinocytes is described, from the proliferative organization to the process of desquamation. PMID:17191035

Houben, E; De Paepe, K; Rogiers, V

2007-01-01

298

Early mouse embryos produce and release factors with transforming growth factor activity  

Microsoft Academic Search

Summary  Previous studies have shown that extracts from mouse embryos at mid and late stages of development contain factors that exhibit\\u000a transforming growth factor activity. The work reported here demonstrates that cultured mouse embryos at significantly earlier\\u000a stages of development produce and release factors that exhibit the characteristic property of transforming growth factors.\\u000a Specifically, the data demonstrate that embryos cultured from

Angie Rizzino

1985-01-01

299

Increased growth factor expression after hepatic and pancreatic resection.  

PubMed

Removal of the primary tumour is suggested to associate with an enhanced tumour growth of residual micrometastases. Recent data focus on growth factors that may be released in response to surgery-stimulating receptors of residual tumour cells. Vascular endothelial (VEGF) and hepatocyte growth factor (HGF) are potent inducers of angiogenesis. The two factors are necessary for wound healing and the promotion of tumour growth. This study was designed to determine growth factor serum levels in patients before, during and after major abdominal surgery. It was recently shown that simultaneous hepatic and pancreatic resection led to poor liver regeneration. As growth factors may be involved in these findings we compared the growth factor levels after liver resection with the levels in patients after pancreatic resection. Forty patients were accrued before hepatopancreatic surgery (hepatic resection n=20 and pancreatic resection n=20). Blood samples were taken from each patient immediately prior to surgery, during the operation and on the postoperative days (POD) 1-3, 5 and 10. To examine the wound fluid, liquid from the wound drains was collected on POD 3. Using ELISA the concentration of the angiogenic cytokines HGF and VEGF165 was determined. After the liver and pancreatic resections, circulating HGF and VEGF165 were increased. We found significantly higher levels of HGF on POD 1-3 (p<0.01), compared to preoperative results with a peak on POD 2. After measuring the postoperative VEGF165 levels we found significantly higher levels of circulating VEGF165 on POD 1-5 (p<0.01) compared to the preoperative levels. On comparing liver with pancreatic resection we did not detect significantly different levels of the two growth factors in the two groups. VEGF165 and HGF concentrations measured during the operation demonstrated no change. HGF and VEGF165 levels detected in the wound fluid on POD 3 were approximately 10 times higher than the preoperative serum levels, respectively. In summary, our data show increased VEGF165 and HGF levels after hepatopancreatic surgery. Notably, the lack of an impact of the type of organ resection on the concentration-time curve of the two growth factors suggest that high postoperative growth factor levels are part of normal wound healing and systemic inflammation. Thus, the proangiogenetic potential of growth factors may account for accelerated tumour growth when residual tumour cells are exposed to high levels of VEGF165 and HGF. PMID:19020737

Justinger, Christoph; Schlüter, Christian; Oliviera-Frick, Vilma; Kopp, Berit; Rubie, Claudia; Schilling, Martin K

2008-12-01

300

Characterizing and engineering antibodies against the epidermal growth factor receptor  

E-print Network

Epidermal growth factor receptor (EGFR) signaling leads to cellular proliferation and migration, and thus EGFR dysregulation can significantly contribute to the survival of tumor cells. Aberrant EGFR signaling due to ...

Chao, Ginger

2008-01-01

301

Visualization of growth factor receptor sites in rat forebrain  

SciTech Connect

It is now known that various growth factors may also act in the central nervous system. Among them, it has recently been shown that epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) may possess trophic effects in the mammalian brain. We report here on the respective autoradiographic distribution of (/sup 125/I)EGF and (/sup 125/I)IGF-I receptor binding sites in the rat brain, both during ontogeny and in adulthood. It appears that (/sup 125/I)EGF sites are mostly found in the rat forebrain during brain development. On the other hand, (/sup 125/I)IGF-I sites are more widely distributed both during ontogeny and in adulthood. These results reveal the plasticity of the expression of EGF and IGF-I receptor sites in the mammalian brain. This could be relevant for the respective role of these two growth factors in the development and maintenance of neuronal function.

Quirion, R.; Araujo, D.; Nair, N.P.; Chabot, J.G.

1988-01-01

302

Epidermal growth factor receptor downregulation by small heterodimeric binding proteins  

E-print Network

No single engineered protein has been shown previously to robustly downregulate epidermal growth factor receptor (EGFR), a validated cancer target. A panel of fibronectin-based domains was engineered to bind with picomolar ...

Hackel, Benjamin J.

303

Secretion of polypeptides related to epidermal growth factor and insulinlike growth factor I by a human teratocarcinoma cell line  

Microsoft Academic Search

Summary  To identify polypeptide growth factors for human teratocarcinoma cells, we studied the malignant ovarian teratoma-derived\\u000a cell line, PA-1, that grew autonomously in serum-free medium. Medium conditioned by undifferentiated PA-1 cells strongly stimulated\\u000a proliferation of the mouse mammary tumor cell line, GR 2H6, which is responsive to epidermal growth factor (EGF) and insulinlike\\u000a growth factor-I (IGF-I). After ammonium sulfate precipitation, PA-1

Naihe Jing; Robert Shiurba; Hiroshi Kitani; Hisaaki Kawakatsu; Yasuhiro Tomooka; Teruyo Sakakura

1991-01-01

304

A family of autocrine growth factors in Mycobacterium tuberculosis  

Microsoft Academic Search

Summary Mycobacterium tuberculosis and its close relative, Mycobacterium bovis (BCG) contain five genes whose predicted products resemble Rpf from Micro- coccus luteus . Rpf is a secreted growth factor, active at picomolar concentrations, which is required for the growth of vegetative cells in minimal media at very low inoculum densities, as well as the resuscitation of dormant cells. We show

Galina V. Mukamolova; Obolbek A. Turapov; Danielle I. Young; Arseny S. Kaprelyants; Douglas B. Kell; Michael Young

305

CRITICAL FACTORS CONTROLLING VEGETATION GROWTH ON COMPLETED SANITARY LANDFILLS  

EPA Science Inventory

This study identifies some of the critical factors that affect tree and shrub growth on reclaimed sanitary landfill sites and determines which woody species are adaptable to the adverse growth conditions of such sites. Trees planted at the Edgeboro Landfill, East Brunswick, New J...

306

Expression of transforming growth factor-?1 during diabetic renal hypertrophy  

Microsoft Academic Search

Expression of transforming growth factor-?1 during diabetic renal hypertrophy. Experimental type I diabetes mellitus is characterized by an early increase in kidney weight and glomerular volume, but changes in gene expression accompanying diabetic renal growth have not been fully elucidated. In the current study, total RNA was extracted from renal cortex and isolated glomeruli of streptozotocin-induced diabetic rats 24 hours,

Stuart J Shankland; James W Scholey; Hao Ly; Kerri Thai

1994-01-01

307

Tunable dual growth factor delivery from polyelectrolyte multilayer films  

Microsoft Academic Search

A promising strategy to accelerate joint implant integration and reduce recovery time and failure rates is to deliver a combination of certain growth factors to the integration site. There is a need to control the quantity of growth factors delivered at different times during the healing process to maximize efficacy. Polyelectrolyte multilayer (PEM) films, built using the layer-by-layer (LbL) technique,

Nisarg J. Shah; Mara L. Macdonald; Yvette M. Beben; Robert F. Padera; Raymond E. Samuel; Paula T. Hammond

2011-01-01

308

Vascular Endothelial Growth Factor is a Secreted Angiogenic Mitogen  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic

David W. Leung; George Cachianes; Wun-Jing Kuang; David V. Goeddel; Napoleone Ferrara

1989-01-01

309

Regulation of wound healing by growth factors and cytokines.  

PubMed

Cutaneous wound healing is a complex process involving blood clotting, inflammation, new tissue formation, and finally tissue remodeling. It is well described at the histological level, but the genes that regulate skin repair have only partially been identified. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. However, the roles played by endogenous growth factors have remained largely unclear. Initial approaches at addressing this question focused on the expression analysis of various growth factors, cytokines, and their receptors in different wound models, with first functional data being obtained by applying neutralizing antibodies to wounds. During the past few years, the availability of genetically modified mice has allowed elucidation of the function of various genes in the healing process, and these studies have shed light onto the role of growth factors, cytokines, and their downstream effectors in wound repair. This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds. Most importantly, we also report on genetic studies addressing the functions of endogenous growth factors in the wound repair process. PMID:12843410

Werner, Sabine; Grose, Richard

2003-07-01

310

Keratinocyte proinflammatory responses to adherent and nonadherent group A streptococci.  

PubMed Central

The gram-positive bacterium Streptococcus pyogenes (group A streptococcus) is the causative agent of a wide variety of suppurative infections of cutaneous tissues. Previous analyses have demonstrated that the M protein of S. pyogenes is an adhesin that directs the attachment of the streptococcus to keratinocytes in the skin. In this study, we have examined keratinocyte function in response to S. pyogenes and found that adherent versus nonadherent streptococci promote distinct patterns of expression of several proinflammatory molecules and keratinocyte cell fate. When analyzed by a quantitative reverse transcriptase PCR method, infection of cultured HaCaT keratinocytes with adherent, but not nonadherent, streptococci resulted in increased expression of mRNA for the cytokines interleukin-1alpha (IL-1alpha), IL-1beta, and IL-8 but neither infection induced expression of tumor necrosis factor alpha. In contrast, both adherent and nonadherent S. pyogenes induced expression of IL-6 and each promoted synthesis and release of prostaglandin E2 (PGE2). However, considerably greater levels of IL-6 expression were stimulated by adherent streptococci relative to nonadherent streptococci and the kinetics of PGE2 release in response to nonadherent streptococci was delayed compared to the response to adherent streptococci. Staining with the fluorescent probe ethidium homodimer-1 revealed that keratinocyte membranes were rapidly damaged upon infection with adherent streptococci but were not damaged by nonadherent streptococci. Finally, treatments which inhibited streptococcal metabolism completely blocked the ability of adherent streptococci to elicit responses. These data suggest that expression of an adhesin is a strategy used by S. pyogenes to modulate keratinocyte responses during infection of the skin and implicate additional streptococcal products in these signaling interactions. PMID:9169741

Wang, B; Ruiz, N; Pentland, A; Caparon, M

1997-01-01

311

Transregulation of Leukemia Inhibitor Factor Receptor Expression and Function by Growth Factors in Neuroblastoma Cells  

PubMed Central

The cytokines that signal through the leukemia inhibitory factor (LIF) receptor are members of the neuropoietic cytokine family and have varied and numerous roles in the nervous system. In this report we have determined the effects of growth factor stimulation on LIF receptor (LIFR) expression and signal transduction in the human neuroblastoma cell line NBFL. We show here that stimulation of NBFL cells with either epidermal growth factor or fibroblast growth factor decreases the level of LIFR in an extracellular signal-regulated kinase (Erk)1/2-dependent manner and that this downregulation is due to an increase in the apparent rate of lysosomal LIFR degradation. Growth factor-induced decreases in LIFR level inhibit both LIF-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3) and LIFR-mediated gene induction. We also show that Ser1044 of LIFR, which we have previously shown to be phosphorylated by Erk1/2, is required for the inhibitory effects of growth factors. Neurons are exposed to varying combinations and concentrations of growth factors and cytokines that influence their growth, development, differentiation and repair in vivo. These findings demonstrate that LIFR expression and signaling in neuroblastoma cells can be regulated by growth factors that are potent activators of the mitogen activated protein kinase pathway, and thus illustrate a fundamental mechanism that underlies cross-talk between receptor tyrosine kinase and neuropoietic cytokine signaling pathways. PMID:18624908

Port, Martha D.; Laszlo, George S.; Nathanson, Neil M.

2008-01-01

312

Tumor-necrosis-factor-induced fibroblast growth factor-1 acts as a survival factor in a transformed endothelial cell line.  

PubMed Central

Endothelial cells undergo apoptosis after withdrawal of growth factors, alterations in the extracellular matrix, or exposure to cytokines. Here we report that tumor necrosis factor (TNF)-alpha induces apoptosis of human endothelial cells derived from the umbilical vein in a dose-dependent fashion. Apoptosis is triggered through a pathway that is independent from the levels of Bcl-2. On the contrary, TNF stimulates the growth of spontaneously transformed human umbilical vein endothelial cells. This proliferative effect is mediated through the up-regulation of fibroblast growth factor-1 by TNF. The addition of specific fibroblast growth factor-1 antisense oligonucleotides inhibits TNF-induced fibroblast growth factor-1 expression, thus inhibiting the growth and triggering apoptosis of spontaneously transformed human umbilical vein endothelial cells. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:8780398

Maier, J. A.; Morelli, D.; Ménard, S.; Colnaghi, M. I.; Balsari, A.

1996-01-01

313

The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes.  

PubMed

Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm (Biogen Idec, Cambridge, MA), licensed in Germany since 1994 for the treatment of moderate-to-severe psoriasis. Psoriasis is a common inflammatory hyperproliferative skin disorder that involves cross-talk between different cell types, including immune cells and keratinocytes. Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation, and inflammation, with the psoriatic cytokine network maintained by communication between immune cells and keratinocytes. Recently, there is increasing evidence regarding the pivotal role of keratinocytes in mediating the disease process, and these cells can be regarded as safe therapeutic targets. From the data available on human subjects treated with Fumaderm, MMF is an effective antipsoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [(3)H]thymidine incorporation into DNA, indicating a direct antiproliferative action on keratinocytes. MMF significantly increased the protein level of keratin 10, the early keratinocyte differentiation marker, and the activity of transglutaminase, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocytes, MMF significantly inhibited the expression of the proinflammatory cytokines, tumor necrosis factor-? (TNF?), interleukin-6, and interleukin-1? as well as the production of TNF?. Our results support the notion that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent. PMID:25332455

Helwa, Inas; Patel, Ravi; Karempelis, Peter; Kaddour-Djebbar, Ismail; Choudhary, Vivek; Bollag, Wendy B

2015-01-01

314

Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis.  

PubMed

Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats. PMID:25206472

Chen, Zhihong; Yang, Songhe; He, Yaqiang; Song, Chengjun; Liu, Yongping

2013-07-01

315

Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis  

PubMed Central

Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats. PMID:25206472

Chen, Zhihong; Yang, Songhe; He, Yaqiang; Song, Chengjun; Liu, Yongping

2013-01-01

316

Making a tooth: growth factors, transcription factors, and stem cells  

Microsoft Academic Search

Mammalian tooth development is largely dependent on sequential and reciprocal epithelial-mesenchymal interactions. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of odontogenic tissues. Multiple signaling molecules, including BMPs, FGFs, Shh, and Wnt proteins, have been implicated in mediating these tissue interactions. Transcription factors participate in epithelial-mesenchymal interactions via linking the

Yan Ding ZHANG; Zhi CHEN; Yi Qiang SONG; Chao LIU; Yi Ping CHEN

2005-01-01

317

Cell surface fibroblast growth factor and epidermal growth factor receptors are permanently lost during skeletal muscle terminal differentiation in culture  

Microsoft Academic Search

One characteristic of skeletal muscle differentiation is the conversion of proliferating cells to a population that is irreversibly postmitotic. This de- velopmental change can be induced in vitro by depriv- ing the cultures of specific mitogens such as fibro- blast growth factor (FGF). Analysis of cell surface FGF receptor (FGFR) in several adult mouse muscle cell lines and epidermal growth

Bradley B. Olwin; Stephen D. Hauschka

1988-01-01

318

Influences of epidermal growth factor and insulin-like growth factor-I on bovine blastocyst development in vitro  

Microsoft Academic Search

Experiments were carried out to investigate putative beneficial effects of adding epidermal growth factor (EGF) or insulin-like growth factor-I (IGF-I) for bovine embryo culture in chemically defined media. Presumptive zygotes (18h post-insemination) were randomly assigned to culture treatments. In experiment 1, treatments involved additions of recombinant human EGF to provide concentrations of 0ng (control), 1, 5, and 25ng\\/ml. No differences

S Sirisathien; H. J Hernandez-Fonseca; B. G Brackett

2003-01-01

319

Receptors for epidermal growth factor and insulin-like growth factor-l on preimplantation trophoderm of the pig  

Microsoft Academic Search

Summary 125 I-labeUed epidermal growth factor (125I-EGF) and 125 I-labeUed insulin-like growth factor-I ( 125 I-IGF-I) bound to trophoderm cells from pig blastocysts obtained on days 15-19 of pregnancy. Specific binding was detected on freshly isolated cell suspensions and on cells cultured for several days. The binding of 12SI-EGF was inhibited by increasing concentrations of EGF, but not by various

A. N. CORPS; D. R. BRIGSTOCK; C. J. LITTLEWOOD; K. D. BROWN

320

Connective tissue growth factor mediates transforming growth factor b-induced collagen synthesis: down- regulation by cAMP  

Microsoft Academic Search

Connective tissue growth factor (CTGF) is a cysteine-rich peptide synthesized and secreted by fibroblastic cells after activation with transforming growth factor beta (TGF-b) that acts as a downstream mediator of TGF-b-induced fibroblast proliferation. We performed in vitro and in vivo studies to determine whether CTGF is also essential for TGF-b-induced fibroblast collagen synthesis. In vitro studies with normal rat kidney

MATTHEW R. DUNCAN; KEN S. FRAZIER; SUSAN ABRAMSON; SHAWN WILLIAMS; HELENE KLAPPER; XINFAN HUANG; GARY R. GROTENDORST

321

Regulation of fibroblast growth factor-23 in chronic kidney disease  

Microsoft Academic Search

Background. Fibroblast growth factor-23 (FGF23) is a circulating factor that regulates the renal reabsorption of inorganic phosphate (Pi) and is increased in chronic kidney disease (CKD). The aim of the current investigation was to study the regulation of FGF23 in CKD subjects with various degree of renal function. As such, we analysed the relationship between FGF23, Pi, calcium, parathyriod hormone

Per-Anton Westerberg; Torbjorn Linde; Bjorn Wikstrom; Osten Ljunggren; Mats Stridsberg; Tobias E. Larsson

2007-01-01

322

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice  

PubMed Central

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin-induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis. PMID:24503019

Schäfer, Matthias; Willrodt, Ann-Helen; Kurinna, Svitlana; Link, Andrea S; Farwanah, Hany; Geusau, Alexandra; Gruber, Florian; Sorg, Olivier; Huebner, Aaron J; Roop, Dennis R; Sandhoff, Konrad; Saurat, Jean-Hilaire; Tschachler, Erwin; Schneider, Marlon R; Langbein, Lutz; Bloch, Wilhelm; Beer, Hans-Dietmar; Werner, Sabine

2014-01-01

323

Growth factors are released by mechanically wounded endothelial cells  

PubMed Central

Growth factors may be required at sites of mechanical injury and normal wear and tear in vivo, suggesting that the direct action of mechanical forces on cells could lead to growth factor release. Scraping of cells from the tissue culture substratum at 37 degrees C was used to test this possibility. We show that scraping closely mimics in vitro both the transient plasma membrane wounds observed in cells subject to mechanical forces in vivo (McNeil, P. L., and S. Ito. 1989. Gastroenterology. 96:1238-1248) and the transient plasma membrane wounds shown here to occur in endothelial cells under normal culturing conditions. Scraping of endothelial cells from the culturing substratum released into the culture medium a potent growth-promoting activity for Swiss 3T3 fibroblasts. Growth-promoting activity was released rapidly (within 5 min) after scraping but was not subsequently degraded by the endothelial cells for at least 24 h thereafter. A greater quantity of growth-promoting activity was released by cells scraped 4 h after plating than by those scraped 4 or 7 d afterwards. Thus release is not due to scraping-induced disruption of extracellular matrix. Release was only partially cold inhibitable, was poorly correlated with the level of cell death induced by scraping, and did not occur when cells were killed with metabolic poisons. These results suggest that mechanical disruption of plasma membrane, either transient or permanent, is the essential event leading to release. A basic fibroblast growth factor- like molecule and not platelet-derived growth factor appears to be partially responsible for the growth-promoting activity. We conclude that one biologically relevant route of release of basic fibroblast growth factor, a molecule which lacks the signal peptide sequence for transport into the endoplasmic reticulum, could be directly through mechanically induced membrane disruptions of endothelial cells growing in vivo and in vitro. PMID:2760113

1989-01-01

324

DNA repair in cultured keratinocytes  

SciTech Connect

Most of our understanding of DNA repair mechanisms in human cells has come from the study of these processes in cultured fibroblasts. The unique properties of keratinocytes and their pattern of terminal differentiation led us to a comparative examination of their DNA repair properties. The relative repair capabilities of the basal cells and the differentiated epidermal keratinocytes as well as possible correlations of DNA repair capacity with respect to age of the donor have been examined. In addition, since portions of human skin are chronically exposed to sunlight, the repair response to ultraviolet (UV) irradiation (254 nm) when the cells are conditioned by chronic low-level UV irradiation has been assessed. The comparative studies of DNA repair in keratinocytes from infant and aged donors have revealed no significant age-related differences for repair of UV-induced damage to DNA. Sublethal UV conditioning of cells from infant skin had no appreciable effect on either the repair or normal replication response to higher, challenge doses of UVL. However, such conditioning resulted in attenuated repair in keratinocytes from adult skin after UV doses above 25 J/m2. In addition, a surprising enhancement in replication was seen in conditioned cells from adult following challenge UV doses.

Liu, S.C.; Parsons, S.; Hanawalt, P.C.

1983-07-01

325

Cytosolic StAR-related lipid transfer domain 4 (STARD4) protein influences keratinocyte lipid phenotype and differentiation status  

Microsoft Academic Search

Terminally differentiating keratinocytes actively synthesize and accumulate cholesterol, which is a key constituent of intercellular lipid lamellae which contribute to the epidermal permeability barrier. While the pathway for cholesterol biosynthesis is established, intracellular transport mechanisms for this lipid are poorly understood, despite their importance in regulating organelle sterol content, keratinocyte differentiation status and the activity of lipid-responsive transcription factors involved

H. M. Elbadawy; Faye Borthwick; Catherine Wright; Patricia E. M. Martin; Annette Graham

2011-01-01

326

Glioma Inhibition by HGF\\/NK2, an Antagonist of Scatter Factor\\/Hepatocyte Growth Factor  

Microsoft Academic Search

Strategies that antagonize growth factor signaling are attractive candidates for the biological therapy of brain tumors. HGF\\/NK2 is a secreted truncated splicing variant and potential antagonist of scatter factor\\/hepatocyte growth factor (SF\\/HGF), a multifunctional cytokine involved in the malignant progression of solid tumors including glioblastoma. U87 human malignant glioma cells that express an autocrine SF\\/HGF stimulatory loop were transfected with

Christopher Guerin; Carey Luddy; Roger Abounader; Bachchu Lal; John Laterra

2000-01-01

327

Growth factors and their receptors as determinants in the proliferation and metastasis of human prostate cancer  

Microsoft Academic Search

Prostate adenocarcinoma, the most common tumor occuring among North American men, preferentially metastasizes to bone, where it characteristically forms osteoblastic lesions. The following growth regulatory factors are expressed in some human prostate cancers and\\/or established cell lines: epidermal growth factor (EGF), transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor (bFGF), and insulin-like growth factor. Some of

Joy L. Ware

1993-01-01

328

Nerve growth factor binding domain of the nerve growth factor receptor  

SciTech Connect

A structural analysis of the rat low-affinity nerve growth factor (NGF) receptor was undertaken to define the NGF binding domain. Mutant NGF receptor DNA constructs were expressed in mouse fibroblasts or COS cells, and the ability of the mutant receptors to bind NGF was assayed. In the first mutant, all but 16 amino acid residues of the intracellular domain of the receptor were removed. This receptor bound NGF with a K{sub d} comparable to that of the wild-type receptor. A second mutant contained only the four cysteine-rich sequences from the extracellular portion of the protein. This mutant was expressed in COS cells and the resultant protein was a secreted soluble form of the receptor that was able to bind NGF. Two N-terminal deletions, in which either the first cystein-rich sequence or the first and part of the second cystein-rich sequences were removed, bound NGF. However, a mutant lacking all four cysteine-rich sequences was unable to bind NGF. These results show that the four cysteine-rich sequences of the NGF receptor contain the NGF binding domain.

Welcher, A.A.; Bitler, C.M.; Radeke, M.J.; Shooter, E.M. (Stanford Univ. School of Medicine, CA (United States))

1991-01-01

329

Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages.  

PubMed

To localize epidermal growth factor (EGF) receptors in normal human epidermis and other skin structures, two different light microscopic methods were used. EGF binding [( 125I]EGF/R) to the extracellular portion of the EGF receptor was studied by incubating intact skin samples with [125I]EGF, sectioning the tissues, and performing autoradiography. Immunoreactive EGF receptor molecules (IR-EGF/R) were localized with a mono-specific anti-EGF receptor antibody using a 2-step indirect immunocytochemical method (horseradish peroxidase) and detergent permeabilized tissues. This latter method measured the total pool of EGF receptors: occupied and/or internalized forms, precursor forms, and partially degraded forms of the EGF receptor that retain immunoreactivity. Both the [125I]EGF/R and IR-EGF/R localization studies indicated that EGF receptors were present in basal epidermal keratinocytes, sebocytes, outer root sheath cells in hair follicles, smooth muscle cells of arrector pili muscles, and dermal arteries. The highest levels of [125I]EGF/R and IR-EGF/R were found in the dermal ducts of eccrine sweat glands. The distribution of both [125I]EGF/R and IR-EGF/R was not consistent with the concept that EGF exclusively is involved in cellular division and proliferation in normal human epidermis and its appendages, i.e., EGF receptors were also found in tissues that do not undergo rapid proliferation. The present study indicates that EGF may have a more complex regulatory role in the skin than was previously thought. PMID:6092481

Nanney, L B; Magid, M; Stoscheck, C M; King, L E

1984-11-01

330

In Vivo Detection of Human Vascular Endothelial Growth Factor Promoter Activity in Transgenic Mouse Skin  

PubMed Central

We have generated transgenic mice expressing green fluorescent protein (GFP) driven by 2.453-kb (?2,362 to +91) of the 5?-upstream region of the human vascular endothelial growth factor (VEGF) promoter to monitor changes of VEGF gene transcription in situ. Neonatal transgenic mice exhibited GFP-derived fluorescence in tissues that have been previously reported to express VEGF mRNA expression, including lung, cartilage, and brain. In normal skin during postnatal development, moderate fluorescence was observed in the upper epidermis and, more prominently, in the outer root sheath keratinocytes of hair follicles. Strong up-regulation of GFP fluorescence was observed in the hyperplastic epidermis of the wound edge at 48 hours after wounding, whereas little GFP fluorescence was detected in the dermis. In situ hybridization confirmed an identical expression pattern of VEGF mRNA in these wounds. Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced strong VEGF-GFP expression in suprabasal epidermis. Little or no fibroblast-derived fluorescence was seen both in the wound model and after TPA application. By confocal laser microscopy, increased GFP fluorescence was detectable in the epidermis of intact mouse ear skin as early as 6 hours after topical TPA treatment. Importantly, GFP fluorescence was also measurable in the skin of living transgenic mice. These results resolve the present controversy regarding the ability of VEGF-GFP transgenic mouse models to correctly reflect established patterns of VEGF expression, and show the model to be a powerful tool for the in vivo monitoring of VEGF gene expression. PMID:10880381

Kishimoto, Jiro; Ehama, Ritsuko; Ge, Yimin; Kobayashi, Takashi; Nishiyama, Toshio; Detmar, Michael; Burgeson, Robert E.

2000-01-01

331

Comparative effects of heparin-binding epidermal growth factor-like growth factor on the growth of cultured human uterine leiomyoma cells and myometrial cells  

Microsoft Academic Search

BACKGROUND: The objective of this study was to investigate the comparative effects of heparin-binding epider- mal growth factor-like growth factor (HB-EGF) on the growth of cultured human leiomyoma cells and myometrial cells. METHODS: Isolated cells were subcultured in Phenol Red-free Dulbecco's modified Eagle's medium sup- plemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free

Jiayin Wang; Noriyuki Ohara; Shigeki Takekida; Qin Xu; Takeshi Maruo

2005-01-01

332

Hypoxia-Mediated Induction of Acidic\\/Basic Fibroblast Growth Factor and Platelet-Derived Growth Factor in Mononuclear Phagocytes Stimulates Growth of Hypoxic Endothelial Cells  

Microsoft Academic Search

Wound repair and tumor vascularization depend upon blood vessel growth into hypoxic tissue. Although hypoxia slows endothelial cell (EC) proliferation and suppresses EC basic fibroblast growth factor (bFGF) expression, we report that macrophages (MPs) exposed to PO_2≈ 12-14 torr (1 torr = 133.3 Pa) synthesize and release in a time-dependent manner platelet-derived growth factor (PDGF) and acidic\\/basic FGFs (a\\/bFGFs), which

Keisuke Kuwabara; Satoshi Ogawa; Masayasu Matsumoto; Shin Koga; Matthias Clauss; David J. Pinsky; Peter Lyn; Jeffrey Leavy; Larry Witte; Jacqueline Joseph-Silverstein; Martha B. Furie; Gabriella Torcia; Federico Cozzolino; Takenobu Kamada; David M. Stern

1995-01-01

333

The Effects of Insulin-Like Growth Factor-1 Gene Therapy and Cell Transplantation on Rat Acute Wound Model  

PubMed Central

Background: Wound healing is a complex process. Different types of skin cells, extracellular matrix and variety of growth factors are involved in wound healing. The use of recombinant growth factors in researches and production of skin substitutes are still a challenge. Objectives: Much research has been done on the effects of gene therapy and cell therapy on wound healing. In this experimental study, the effect of insulin-like growth factor (IGF-1) gene transfer in fibroblast cells was assessed on acute dermal wound healing. Materials and Methods: Fibroblasts were cultured and transfected with IGF-1. Lipofectamine 2000 was used as a reagent of transfection. Transgene expression levels were measured by the enzyme linked immunosorbent assay (ELISA). To study in vivo, rats (weighing 170-200 g) were randomly divided into three groups (five/group) and full-thickness wounds were created on the dorsum region. Suspensions of transfected fibroblast cells were injected into the wound and were compared with wounds treated with native fibroblast cells and normal saline. For the microscopic examination, biopsy was performed on day seven. Results: In vitro, the maximum expression of IGF1 (96.95 pg/mL) in transfected fibroblast cells was 24 hours after gene transfer. In vivo, it was clear that IGF-1 gene therapy caused an increase in the number of keratinocyte cells during the wound healing process (mean of group A vs. group B with P value = 0.01, mean of group A vs. group C with P value = 0.000). Granulation of tissue formation in the transfected fibroblast group was more organized when compared with the normal saline group and native fibroblast cells. Conclusions: This study indicated that the optimization of gene transfer increases the expression of IGF-1. High concentrations of IGF-1, in combination with cell therapy, have a significant effect on wound healing. PMID:25558384

Talebpour Amiri, Fereshteh; Fadaei Fathabadi, Fatemeh; Mahmoudi Rad, Mahnaz; Piryae, Abbas; Ghasemi, Azar; Khalilian, Alireza; Yeganeh, Farshid; Mosaffa, Nariman

2014-01-01

334

Epiprofin orchestrates epidermal keratinocyte proliferation and differentiation.  

PubMed

The basal layer of the epidermis contains stem cells and transit amplifying cells that rapidly proliferate and differentiate further into the upper layers of the epidermis. A number of molecules have been identified as regulators of this process, including p63 (also known as tumor protein 63) and Notch1. However, little is known about the mechanisms that regulate the transitions from stem cell to proliferating or differentiating transit amplifying cell. Here, we demonstrate that epiprofin (Epfn, also known as Sp6) plays crucial distinct roles in these transition stages as a cell cycle regulator and a transcription factor. Epfn knockout mice have a thickened epidermis, in which p63-expressing basal cells form multiple layers owing to the accumulation of premature transit amplifying cells with reduced proliferation and a reduction in the number of differentiating keratinocytes expressing Notch1. We found that low levels of Epfn expression increased the proliferation of human immortalized keratinocyte (HaCaT) cells by increasing EGF responsiveness and superphosphorylation of Rb. By contrast, high levels of Epfn expression promoted cell cycle exit and differentiation, by reducing E2F transactivation and inducing Notch1 expression. Our findings identify multiple novel functions of Epfn in epidermal development. PMID:25344255

Nakamura, Takashi; Yoshitomi, Yasuo; Sakai, Kiyoshi; Patel, Vyomesh; Fukumoto, Satoshi; Yamada, Yoshihiko

2014-12-15

335

Nutrients versus growth factors in mTORC1 activation  

PubMed Central

Growth factors and nutrients regulate the mechanistic target of rapamycin complex 1 (mTORC1) by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. In contrast to the picture for growth factor signaling, the means by which nutrient availability leads to mTORC1 activation have remained elusive until recently, with the discovery of the Rag GTPases upstream of mTORC1. The Rag GTPases recruit mTORC1 to the outer lysosomal surface, where growth factor signaling and nutrient signaling converge on mTORC1 activation. A mouse model of constitutive RagA activity has revealed qualitative differences between growth factor- and nutrient– dependent regulation of mTORC1. Regulation of mTORC1 activity by the Rag GTPases in vivo is key for enduring early neonatal fasting, showing its importance for mammalian physiology. PMID:23863153

Efeyan, Alejo; Sabatini, David M

2013-01-01

336

A Two-Stage, p16INK4A- and p53Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status  

Microsoft Academic Search

With increasing frequency during serial passage in culture, primary human keratinocytes express p16INK4A (p16) and undergo senescence arrest. Keratinocytes engineered to express hTERT maintain long telomeres but typically are not immortalized unless, by mutation or other heritable event, they avoid or greatly reduce p16 expression. We have confirmed that keratinocytes undergo p16-related senescence during growth in culture, whether in the

James G. Rheinwald; William C. Hahn; Matthew R. Ramsey; Jenny Y. Wu; Zongyou Guo; Hensin Tsao; Michele De Luca; Caterina Catricala; Kathleen M. O'Toole

337

Monokines and platelet-derived growth factor modulate prostanoid production in growth arrested, human mesangial cells  

Microsoft Academic Search

Monokines and platelet-derived growth factor modulate prostanoid production in growth arrested, human mesangial cells. Previous studies have demonstrated considerable prostanoid production by cultured proliferating rat mesangial cells (MC). In this study, human mesangial cells (HMC) were examined during serum-free culture in which the cells were reversibly growth arrested and did not suffer obvious irreversible functional changes. Non-stimulated cells released 2

Jürgen Floege; Nicholas Topley; Klaus Wessel; Volkhard Kaever; Heinfried Radeke; Jürgen Hoppe; Tadamitsu Kishimoto; Klaus Resch

1990-01-01

338

Insulin Resistance and Insulin-Like Growth Factors in Children with Intrauterine Growth Retardation  

Microsoft Academic Search

Aims: To investigate (a) the prevalence of insulin resistance in children with intrauterine growth retardation (IUGR); (b) whether catch-up growth is associated with a higher risk of insulin resistance; (c) the insulin-like growth factor (IGF) system status. Methods: 49 children with IUGR aged 9.1 ± 3.3 years underwent anthropometric measurements, and assessment of insulin resistance and IGF system parameters. A

Stefano Canfarani; Caterina Geremia; Daniela Germani; Giuseppe Scirè; Arianna Maiorana; Sergio Boemi

2001-01-01

339

Growth Hormone and Insulin-Like Growth Factors as Anabolic Therapies for Osteoporosis  

Microsoft Academic Search

Growth hormone (GH) and insulin-like growth factors (IGFs) play a central role in skeletal growth and bone remodeling. In vitro, both agents display anabolic properties, and patients with acromegaly exhibit increased bone mass. Recent in vivo studies have demonstrated profound activation of bone remodeling that lasted for months after a single 1-week dose of GH or IGF-I. Despite these positive

Erik F. Eriksen; Mustapha Kassem; Kim Brixen

1993-01-01

340

Advances in pubertal growth and factors influencing it: Can we increase pubertal growth?  

PubMed Central

Puberty is a period of development characterized by partially concurrent changes which includes growth acceleration, alteration in body composition and appearance of secondary sex characteristics. Puberty is characterized by an acceleration and then deceleration in skeletal growth. The initiation, duration and amount of growth vary considerably during the growth spurt. Pubertal growth and biological maturation are dynamic processes regulated by a variety of genetic and environmental factors. Changes in skeletal maturation and bone mineral accretion concomitant with the stage of pubertal development constitute essential components in the evaluation of growth during this pubertal period. Genetic, endocrine and nutritional factors and ethnicity contribute variably to the amount of growth gained during this important period of rapid changes. Many studies investigated the possibility of increasing pubertal growth to gain taller final adult height in adolescents with idiopathic short stature (ISS). The pattern of pubertal growth, its relation to sex maturity rating and factors affecting them has been addressed in this review. The results of different trials to increase final adult height of adolescents using different hormones have been summarized. These data enables Endocrinologists to give in-depth explanations to patients and families about the efficacy and clinical significance as well as the safety of using these therapies in the treatment of adolescents with ISS. PMID:25538878

Soliman, Ashraf; De Sanctis, Vincenzo; Elalaily, Rania; Bedair, Said

2014-01-01

341

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia  

PubMed Central

The epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development and homeostasis. Its functions in the sebaceous gland (SG), however, remain poorly characterized. In this study, using a transgenic mouse line with tissue-specific and inducible expression of the EGFR ligand epigen, we showed that increased activation of the EGFR in skin keratinocytes results in enlarged SGs and increased sebum production. The phenotype can be reverted by interrupting transgene expression and is EGFR dependent, as gland size and sebum levels return to normal values after crossing to the EGFR-impaired mouse line Wa5. Intriguingly, however, the SG enlargement appears only if EGFR activation occurs before birth. Importantly, the enlarged sebaceous glands are associated with an increased expression of the transcription factor MYC and of the transmembrane proteins LRIG1, an established negative-feedback regulator of the EGFR/ERBB tyrosine kinase receptors and a stem cell marker. Our findings identify EGFR signaling as a major pathway determining SG activity and suggest a functional relationship between the EGFR/ERBB system and MYC/LRIG1 in the commitment of stem cells toward specific progenitor cell types, with implications for our understanding of their role in tissue development, homeostasis, and disease. PMID:24891618

Dahlhoff, Maik; Frances, Daniela; Kloepper, Jennifer E.; Paus, Ralf; Schäfer, Matthias; Niemann, Catherin

2014-01-01

342

Local application of growth factors (insulin-like growth factor-1 and transforming growth factor-?1) from a biodegradable poly( d,l-lactide) coating of osteosynthetic implants accelerates fracture healing in rats  

Microsoft Academic Search

In vitro and in vivo studies have demonstrated an osteoinductive effect of growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-?1 (TGF-?1). However, for therapeutic use in fracture treatment, questions remain with regard to the local application of these proteins. A controlled, local release of growth factors from a biodegradable polylactide coating of osteosynthetic implants may have

G Schmidmaier; B Wildemann; H Bail; M Lucke; T Fuchs; A Stemberger; A Flyvbjerg; N. P Haas; M Raschke

2001-01-01

343

Exercise and Circulating Insulin-Like Growth Factor I  

Microsoft Academic Search

Determinations of serum concentrations of total insulin-like growth factor I (tIGF-I) are important in the diagnosis, monitoring of treatment and safety evaluation of patients with growth disorders and\\/or metabolic disease. It is well established that tIGF-I status varies over time. Changes in tIGF-I levels in relation to an acute bout of exercise or repeated bouts, known as training, are likely

Ulrika Berg; Peter Bang

2004-01-01

344

Insulin-like growth factor-1: roles in androgenetic alopecia.  

PubMed

Of all the cytokines or growth factors that have been postulated to play a role in hair follicle, insulin-like growth factor-1 (IGF-1) is known to be regulated by androgens. However, how IGF-1 is altered in the balding scalp has not yet been investigated. In this study, expressions of IGF-1 and its binding proteins by dermal papilla (DP) cells obtained from balding versus non-balding hair follicles were quantified using growth factor array. DP cells from balding scalp follicles were found to secrete significantly less IGF-1, IGFBP-2 and IGFBP-4 (P < 0.05) than their non-balding counterparts. Our data confirmed that the downregulation of IGF-1 may be one of the important mechanisms contributing to male pattern baldness. PMID:24499417

Panchaprateep, Ratchathorn; Asawanonda, Pravit

2014-03-01

345

Epidermal growth factor, from gene organization to bedside  

PubMed Central

In 1962, epidermal growth factor (EGF) was discovered by Dr. Stanley Cohen while studying nerve growth factor (NGF). It was soon recognized that EGF is the prototypical member of a family of peptide growth factors that activate the EGF receptors, and that the EGF/EGF receptor signaling pathway plays important roles in proliferation, differentiation and migration of a variety of cell types, especially in epithelial cells. After the basic characterization of EGF function in the first decade or so after its discovery, the studies related to EGF and its signaling pathway have extended to a broad range of investigations concerning its biological and pathophysiological roles in development and in human diseases. In this review, we briefly describe the gene organization and tissue distribution of EGF, with emphasis on its biological and pathological roles in human diseases. PMID:24513230

Zeng, Fenghua; Harris, Raymond C.

2014-01-01

346

Growth factors with heparin binding affinity in human synovial fluid  

SciTech Connect

Synovial effusions were obtained from the knees of 15 subjects with joint trauma, menisceal or ligamentous injury, or osteoarthritis. Heparin-Sepharose affinity chromatography of these synovial fluids revealed, in general, three major peaks of mitogenic activity as measured by incorporation of /sup 3/H-thymidine into 3T3 cells. Gradient elution patterns showed activities at 0.5M NaCl, which is characteristic of platelet derived growth factor, and at 1.1 M NaCl and 1.6M NaCl, indicative of acidic and basic fibroblast growth factors, respectively. The identities of these mitogenic fractions were confirmed by specific immunologic and receptor-binding assays. The presence of platelet derived, acidic and basic fibroblast growth factors in the synovial fluid may contribute to wound healing in the arthritic joint.

Hamerman, D.; Taylor, S.; Kirschenbaum, I.; Klagsbrun, M.; Raines, E.W.; Ross, R.; Thomas, K.A.

1987-12-01

347

Multiple Transcription Factor Families Regulate Axon Growth and Regeneration  

PubMed Central

Understanding axon regenerative failure remains a major goal in neuroscience, and reversing this failure remains a major goal for clinical neurology. While an inhibitory CNS environment clearly plays a role, focus on molecular pathways within neurons has begun to yield fruitful insights. Initial steps forward investigated the receptors and signaling pathways immediately downstream of environmental cues, but recent work has also shed light on transcriptional control mechanisms that regulate intrinsic axon growth ability, presumably through whole cassettes of gene target regulation. Here we will discuss transcription factors that regulate neurite growth in vitro and in vivo, including p53, SnoN, E47, CREB, STAT3, NFAT, c-Jun, ATF3, Sox11, NF?B, and Kruppel-like factors (KLFs). Revealing the similarities and differences among the functions of these transcription factors may further our understanding of the mechanisms of transcriptional regulation in axon growth and regeneration. PMID:21674813

Moore, Darcie L.; Goldberg, Jeffrey L.

2011-01-01

348

Growth hormone and insulin-like growth factor I concentrations in bulls of various growth hormone genotypes  

Microsoft Academic Search

A leucine\\/valine substitution at amino acid position 127 was identified by the polymerase chain reaction and restriction fragment length polymorphism in the bovine growth hormone gene. Genotyping was performed in 84 AI bulls of three different breeds, in which plasma concentrations of growth hormone (GH) and insulin-like growth factor I (IGF-1) were also measured. Gene frequencies of variants L (leucine)

P. Schlee; R. Graml; E. Schallenberger; D. Schams; O. Rottmann; A. Olbrich-Bludau; F. Pirchner

1994-01-01

349

Endothelin-1 is a transcriptional target of p53 in epidermal keratinocytes and regulates UV induced melanocyte homeostasis  

PubMed Central

Summary Keratinocytes contribute to melanocyte activity by influencing their microenvironment, in part, through secretion of paracrine factors. Here we discovered that p53 directly regulates Edn1 expression in epidermal keratinocytes and controls UV-induced melanocyte homeostasis. Selective ablation of EDN1 in murine epidermis (EDN1ep?/?) does not alter melanocyte homeostasis in newborn skin but decreases dermal melanocytes in adult skin. Results showed that keratinocytic EDN1 in a non-cell autonomous manner controls melanocyte proliferation, migration, DNA damage and apoptosis after UVB irradiation. Expression of other keratinocyte derived paracrine factors did not compensate for the loss of EDN1. Topical treatment with EDN1 receptor (EDNRB) antagonist BQ788 abrogated UV induced melanocyte activation and recapitulated the phenotype seen in EDN1ep?/? mice. Altogether, present studies establish an essential role of EDN1 in epidermal keratinocytes to mediate UV induced melanocyte homeostasis in vivo. PMID:23279852

Hyter, Stephen; Coleman, Daniel J.; Ganguli-Indra, Gitali; Merrill, Gary F.; Ma, Steven; Yanagisawa, Masashi; Indra, Arup K.

2013-01-01

350

Engineering insulin-like growth factor-1 for local delivery.  

PubMed

Insulin-like growth factor-1 (IGF-1) is a small protein that promotes cell survival and growth, often acting over long distances. Although for decades IGF-1 has been considered to have therapeutic potential, systemic side effects of IGF-1 are significant, and local delivery of IGF-1 for tissue repair has been a long-standing challenge. In this study, we designed and purified a novel protein, heparin-binding IGF-1 (Xp-HB-IGF-1), which is a fusion protein of native IGF-1 with the heparin-binding domain of heparin-binding epidermal growth factor-like growth factor. Xp-HB-IGF-1 bound selectively to heparin as well as the cell surfaces of 3T3 fibroblasts, neonatal cardiac myocytes and differentiating ES cells. Xp-HB-IGF-1 activated the IGF-1 receptor and Akt with identical kinetics and dose response, indicating no compromise of biological activity due to the heparin-binding domain. Because cartilage is a proteoglycan-rich environment and IGF-1 is a known stimulus for chondrocyte biosynthesis, we then studied the effectiveness of Xp-HB-IGF-1 in cartilage. Xp-HB-IGF-1 was selectively retained by cartilage explants and led to sustained chondrocyte proteoglycan biosynthesis compared to IGF-1. These data show that the strategy of engineering a "long-distance" growth factor like IGF-1 for local delivery may be useful for tissue repair and minimizing systemic effects. PMID:18285400

Tokunou, Tomotake; Miller, Rachel; Patwari, Parth; Davis, Michael E; Segers, Vincent F M; Grodzinsky, Alan J; Lee, Richard T

2008-06-01

351

Growth factor receptors signaling in glioblastoma cells: therapeutic implications  

Microsoft Academic Search

In this study, we investigated the protein expression of platelet-derived growth factor receptor (PDGFR), insulin like growth\\u000a factor-1 receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1\\/2) in five\\u000a primary glioblastoma (GB), with a view to their possible use as therapeutic targets. Our results demonstrated that appreciable\\u000a levels of these proteins could be detected in the analysed GB cell

Mia Carapancea; Oana Alexandru; Ani S. Fetea; Laura Dragutescu; Juan Castro; Ada Georgescu; A. Popa-Wagner; Magnus L. Bäcklund; Rolf Lewensohn; Anica Dricu

2009-01-01

352

Cytokines and growth factors which regulate bone cell function  

NASA Astrophysics Data System (ADS)

Everybody knows that growth factors are most important in making bone. Hormones enhance bone formation from a long distance. Growth factors promote bone formation as an autocrine or paracrine factor in nearby bone. BMP-2 through BMP-8 are in the TGF-? family. BMP makes bone by enchondral ossification. In bone, IGF-II is most abundant, second, TGF-?, and third IGF-I. TGF-? enhances bone formation mainly by intramembranous ossification in vivo. TGF-? affects both cell proliferation and differentiation, however, TGF-? mainly enhances bone formation by intramembranous ossification. Interestingly, TGF-? is increased by estrogen(E 2), androgen, vitamin D, TGF-? and FGF. IGF-I and IGF-II also enhance bone formation. At present it remains unclear why IGF-I is more active in bone formation than IGF-II, although IGF-II is more abundant in bone compared to IGF-I. However, if only type I receptor signal transduction promotes bone formation, the strong activity of IGF-I in bone formation is understandable. GH, PTH and E 2 promotes IGF-I production. Recent data suggest that hormones containing vitamin D or E 2 enhance bone formation through growth factors. Therefore, growth factors are the key to clarifying the mechanism of bone formation.

Seino, Yoshiki

353

Isolation, cultivation and transfection of human keratinocytes.  

PubMed

Human keratinocytes could be used in the repair of damaged skin, in tissue engineering applications, gene therapy and recently, the generation of iPS cells. We isolated human keratinocytes from foreskin and subsequently cultured them on fibronectin, collagen type I, gelatin and laminin-coated dishes that contained three different types of serum-free medium (epilife, KSM or CnT). We developed improved conditions for efficient transfection of these human keratinocytes by testing three common transfection methods and a GFP plasmid vector. The isolated cells showed typical keratinocyte morphology and expressed the epithelial cell specific antigen, cytokeratin 14. Collagen type 1, epilife medium and lipofectamin 2000 gave the best results for isolation and transfection of human keratinocytes. Our protocol can be used as a reproducible, simple and efficient method for isolation, cultivation and genetic manipulation of human keratinocytes, which may be useful in cell and gene therapy applications. PMID:24323435

Zare, Sona; Zarei, Mohammad Ali; Ghadimi, Tayyeb; Fathi, Fardin; Jalili, Ali; Hakhamaneshi, Mohammad Saeed

2014-04-01

354

Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer  

PubMed Central

Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non–small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed. PMID:20975071

Maki, Robert G.

2010-01-01

355

EMILIN1–?4/?9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation  

PubMed Central

EMILIN1 promotes ?4?1 integrin–dependent cell adhesion and migration and reduces pro–transforming growth factor–? processing. A knockout mouse model was used to unravel EMILIN1 functions in skin where the protein was abundantly expressed in the dermal stroma and where EMILIN1-positive fibrils reached the basal keratinocyte layer. Loss of EMILIN1 caused dermal and epidermal hyperproliferation and accelerated wound closure. We identified the direct engagement of EMILIN1 to ?4?1 and ?9?1 integrins as the mechanism underlying the homeostatic role exerted by EMILIN1. The lack of EMILIN1–?4/?9 integrin interaction was accompanied by activation of PI3K/Akt and Erk1/2 pathways as a result of the reduction of PTEN. The down-regulation of PTEN empowered Erk1/2 phosphorylation that in turn inhibited Smad2 signaling by phosphorylation of residues Ser245/250/255. These results highlight the important regulatory role of an extracellular matrix component in skin proliferation. In addition, EMILIN1 is identified as a novel ligand for keratinocyte ?9?1 integrin, suggesting prospective roles for this receptor–ligand pair in skin homeostasis. PMID:21949412

Danussi, Carla; Petrucco, Alessandra; Wassermann, Bruna; Pivetta, Eliana; Modica, Teresa Maria Elisa; Belluz, Lisa Del Bel; Spessotto, Paola

2011-01-01

356

Exogenous stimulation with Eclipta alba promotes hair matrix keratinocyte proliferation and downregulates TGF-?1 expression in nude mice.  

PubMed

Eclipta alba (L.) Hassk (E. alba) is a traditionally acclaimed medicinal herb used for the promotion of hair growth. However, to the best of our knowledge, no report has been issued to date on its effects on genetically distorted hair follicles (HFs). In this study, we aimed to identify an agent (stimuli) that may be beneficial for the restoration of human hair loss and which may be used as an alternative to synthetic drugs. We investigated the effects of petroleum ether extract (PEE) and different solvent fractions of E. alba on HFs of nude mice. Treatment was performed by topical application on the backs of nude mice and the changes in hair growth patterns were evaluated. Histological analysis was carried out to evaluate the HF morphology and the structural differences. Immunohistochemical (IHC) staining was performed to visualize follicular keratinocyte proliferation. The histological assessments revealed that the PEE-treated skin specimens exhibited prominent follicular hypertrophy. Subsequently, IHC staining revealed a significant increase (p<0.001) in the number of follicular keratinocytes in basal epidermal and matrix cells. Our results also demonstrated that PEE significantly (p<0.001) reduced the levels of transforming growth factor-?1 (TGF-?1) expression during early anagen and anagen-catagen transition. Our results suggest that PEE of E. alba acts as an important exogenous mediator that stimulates follicular keratinocyte proliferation and delays terminal differentiation by downregulating TGF-?1 expression. Thus, this study highlights the potential use of PEE of E. alba in the treatment of certain types of alopecia. PMID:25484129

Begum, Shahnaz; Lee, Mi Ra; Gu, Li Juan; Hossain, Jamil; Sung, Chang Keun

2015-02-01

357

Nuclear Factor YY1 Inhibits Transforming Growth Factor  - and Bone Morphogenetic Protein-Induced Cell Differentiation  

Microsoft Academic Search

Smad proteins transduce transforming growth factor (TGF-) and bone morphogenetic protein (BMP) signals that regulate cell growth and differentiation. We have identified YY1, a transcription factor that positively or negatively regulates transcription of many genes, as a novel Smad-interacting protein. YY1 represses the induction of immediate-early genes to TGF- and BMP, such as the plasminogen activator inhibitor 1 gene (PAI-1)

Keiko Kurisaki; Akira Kurisaki; Ulrich Valcourt; Alexei A. Terentiev; Katerina Pardali; P. ten Dijke; C.-H. Heldin; J. Ericsson; A. Moustakas

2003-01-01

358

Growth factors in the treatment of early osteoarthritis  

PubMed Central

Summary Regenerative medicine is the science that studies the regeneration of biological tissues obtained through use of cells, with the aid of support structures and with biomolecules such as growth factors. As regards the growth factors the PRP, or the platelet-rich plasma, obtained from a withdrawal of autologous blood, concentrating the platelets, represents a safe, economical, easy to prepare and easy to apply source of growth factors. Numerous growth factors are in fact within the platelets and in particular a large number of them have a specific activity on neo-proliferation, on cartilage regeneration and in particular also an antiapoptotic effect on chondroblasts: - The PDGF which regulates the secretion and synthesis of collagen;- The EGF that causes cellular proliferation, endothelial chemotaxis and angiogenesis;- The VEGF that increases angiogenesis and vascular permeability;- The TGF-beta that stimulates the proliferation of undifferentiated MSC, stimulates chemotaxis of endothelial cells and angiogenesis;- The bFGF that promotes the growth and differentiation of chondrocytes and osteoblasts stimulates mitogenesis of mesenchymal cells, chondrocytes and osteoblasts. These properties have led to the development of studies that evaluated the efficacy of treatment of infiltrations in the knee and hip with platelet-derived growth factors. Regarding the knee it was demonstrated that in patients with moderate degree of gonarthrosis, the PRP is able to significantly reduce the pain and improve joint function, both on placebo and towards infiltrations with hyaluronic acid. The success of the treatment was proportional to the age of and inversely proportional to the severity of osteoarthritis according to Kellgren and Lawrence classification. The possibility of infiltrations guided with ultrasound into the hip led us to extend the indications also to hip arthrosis, as already showed by Sanchez. Even in coxarthrosis preliminary results at 6 and 12 months show that a cycle of 3 infiltrations of PRP has significantly decreased the pain and increased range of motion and joint function. PMID:23858307

Civinini, Roberto; Nistri, Lorenzo; Martini, Caterina; Redl, Birgit; Ristori, Gabriele; Innocenti, Massimo

2013-01-01

359

Human Keratinocytes Are Vanilloid Resistant  

Microsoft Academic Search

BackgroundUse of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain\\/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca2+-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular

László Pecze; Kornélia Szabó; Márta Széll; Katalin Jósvay; Krisztián Kaszás; Erzsébet Kúsz; Tamás Letoha; János Prorok; István Koncz; András Tóth; Lajos Kemény; Csaba Vizler; Zoltán Oláh; Leslie B. Vosshall

2008-01-01

360

Functional upregulation of system xc- by fibroblast growth factor-2.  

PubMed

The cystine/glutamate antiporter (system xc-) is a Na(+)-independent amino acid transport system. Disruption of this system may lead to multiple effects in the CNS including decreased cellular glutathione. Since multiple neurological diseases involve glutathione depletion, and disruption of growth factor signaling has also been implicated in these diseases, it is possible that some growth factors effects are mediated by regulation of system xc-. We tested the growth factors fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG), neurotrophin-4 (NT-4), and brain derived neurotrophic factor (BDNF) on system xc- mediated 14C-cystine uptake in mixed neuronal and glial cortical cultures. Only FGF-2 significantly increased cystine uptake. The effect was observed in astrocyte-enriched cultures, but not in cultures of neurons or microglia. The increase was blocked by the system xc- inhibitor (s)-4-carboxyphenylglycine, required at least 12 h FGF-2 treatment, and was prevented by the protein synthesis inhibitor cycloheximide. Kinetic analysis indicated FGF-2 treatment increased the V(max) for cystine uptake while the K(m) remained the same. Quantitative PCR showed an increase in mRNA for xCT, the functional subunit of system xc-, beginning at 3 h of FGF-2 treatment, with a dramatic increase after 12 h. Blocking FGFR1 with PD 166866 blocked the FGF-2 effect. Treatment with a PI3-kinase inhibitor (LY-294002) or a MEK/ERK inhibitor (U0126) for 1 h prior to and during the FGF-2 treatment, each partially blocked the increased cystine uptake. The upregulation of system xc- by FGF-2 may be responsible for some of the known physiological actions of FGF-2. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID:21967732

Liu, Xiaoqian; Resch, Jon; Rush, Travis; Lobner, Doug

2012-02-01

361

Therapeutic potential of growth factors and their antagonists.  

PubMed Central

This article describes studies with four peptides, epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), gastrin-releasing peptide/bombesin (GRP), and gastrin. The mitogenic and anti-secretory activities of EGF/TGF alpha appear to be mediated by a single class of high-affinity membrane receptors but may involve different signal transducing mechanisms. Biological activity of EGF resides in the N-terminal 42 amino acid fragment with the C-terminal undecapeptide determining binding affinity. A parenteral depot formulation of an EGF-related peptide or a small molecule agonist of the EGF receptor could have utility in treating various ulcerative disorders of the gut. Although antagonism of EGF (and thus TGF alpha) receptors and/or transducing mechanisms is frequently cited as a potential therapeutic approach to hyperproliferative diseases, blocking the action of TGF alpha, GRP, or gastrin with neutralizing antibodies or receptor antagonists did not influence the growth of a wide range of solid tumors in nude mice. These findings suggest that, unless tumor growth displays absolute dependency on one particular mitogen, antagonism of a specific growth factor is unlikely to have great effect in cancer therapy. PMID:1341074

Garner, A.

1992-01-01

362

Expression of Nucleostemin, epidermal growth factor and epidermal growth factor receptor in human esophageal squamous cell carcinoma tissues  

Microsoft Academic Search

Objective  To determine the expression of nucleostemin (NS), epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR)\\u000a mRNA in human esophageal squamous cell carcinoma (ESCC) tissues and their association in a human ESCC cell line.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The expression of NS, EGF and EGFR mRNA was determined in paired normal esophageal and ESCC tissues of 62 patients using in\\u000a situ hybridization. The

Gongyuan Zhang; Qiao Zhang; Qinxian Zhang; Lei Yin; Shenglei Li; Kuisheng Cheng; Yunhan Zhang; Honghui Xu; Weidong Wu

2010-01-01

363

Heparin-Binding Epidermal Growth Factor-like Growth Factor/Diphtheria Toxin Receptor in Normal and Neoplastic Hematopoiesis  

PubMed Central

Heparin-binding EGF-like growth factor (HB-EGF) belongs to the EGF family of growth factors. It is biologically active either as a molecule anchored to the membrane or as a soluble form released by proteolytic cleavage of the extracellular domain. HB-EGF is involved in relevant physiological and pathological processes spanning from proliferation and apoptosis to morphogenesis. We outline here the main activities of HB-EGF in connection with normal or neoplastic differentiative or proliferative events taking place primitively in the hematopoietic microenvironment. PMID:23888518

Vinante, Fabrizio; Rigo, Antonella

2013-01-01

364

Proteasome Inhibition by Fellutamide B Induces Nerve Growth Factor Synthesis  

Microsoft Academic Search

SUMMARY Neurotrophic small molecules have the potential to aid in the treatment of neuronal injury and neurode- generative diseases. The natural product fellutamide B, originally isolated from Penicillium fellutanum, potently induces nerve growth factor (NGF) release from fibroblasts and glial-derived cells, although the mechanism for this neurotrophic activity has not been elucidated. Here, we report that fellutamide B potently inhibits

John Hines; Michael Groll; Margaret Fahnestock; Craig M. Crews

2008-01-01

365

An Atomic Resolution Structure for Human Fibroblast Growth Factor 1  

E-print Network

An Atomic Resolution Structure for Human Fibroblast Growth Factor 1 Matthew J. Bernett. The backbone atoms of each structurally conserved region of the symmetry-related subdomains in FGF-1 overlay and Biochemistry, Florida State University, Tallahassee, Florida ABSTRACT A 1.10-Ã? atomic resolution X

Blaber, Michael

366

Chance, Creativity, and the Discovery of the Nerve Growth Factor  

Microsoft Academic Search

This essay analyzes the history of the Nerve Growth Factor (NGF) discovery, relating some of the principles of the theory of scientific creativity to the cognitive and personal qualities of the scientists that participated in the discovery, particulary Rita Levi-Montalcini and Viktor Hamburger. The discovery of NGF is especially attractive for the history of science as it involves chance, luck,

Ana Cecilia Rodríguez de Romo

2007-01-01

367

Immunocytochemical expression of growth factors by odontogenic jaw cysts.  

PubMed Central

AIM: To determine the immunocytochemical pattern of expression of transforming growth factor (TGF) alpha, epidermal growth factor (EGF), and TGF beta in the three most common types of odontogenic jaw cyst. METHODS: Growth factor expression was detected in paraffin wax sections of odontogenic cysts (27 odontogenic keratocysts, 10 dentigerous cysts, and 10 radicular cysts) using a streptavidin-biotin peroxidase technique with monoclonal antibodies directed against TGF alpha (clone 213-4.4) and TGF beta (clone TB21) and a polyclonal antibody directed against EGF (Z-12). RESULTS: The epithelial linings of all cysts showed reactivity for TGF alpha which was mainly localised to basal and suprabasal layers. Odontogenic keratocyst linings expressed higher levels of TGF alpha than those of dentigerous and radicular cysts, with 89% (24/27) of odontogenic keratocysts exhibiting a strong positive reaction compared with 50% (five of 10) of dentigerous and radicular cysts, respectively. EGF reactivity was similar in all cyst groups, weaker than that for TGF alpha and predominantly suprabasal. TGF alpha and EGF were also detected in endothelial cells, fibroblasts and inflammatory cells within the cyst walls. The most intense TGF beta staining in odontogenic cysts was extracellular within the fibrous tissue capsules, irrespective of cyst type. CONCLUSIONS: These results, together with previous studies of EGF receptor, indicate differential expression of TGF alpha, EGF and their common receptor between the different types of odontogenic cyst, suggesting that these growth factors (via autocrine or paracrine, or both, pathways) may be involved in their pathogenesis. Images PMID:9208810

Li, T.; Browne, R. M.; Matthews, J. B.

1997-01-01

368

Transforming growth factor ? as a therapeutic target in systemic sclerosis  

Microsoft Academic Search

Transforming growth factor ? (TGF-?) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-? expression is implicated in the pathogenesis of fibrosis in systemic sclerosis (SSc); thus, TGF-? represents a molecular therapeutic target in this disease. Anti-TGF-? monoclonal antibody has been evaluated in a small trial of early SSc, with disappointing results. Antibodies against the ?v?6 integrin that prevent

Boris Pasche; John Varga

2009-01-01

369

Stimulation of Hamster Sebaceous Glands by Epidermal Growth Factor  

Microsoft Academic Search

Subcutaneous injection of epidermal growth factor (EGF) into the pinna of adult female and castrated male Syrian hamsters resulted in an increase in the number of cells per sebaceous gland unit. The effect of EGF on the sebaceous cell number was localized to the treated ear and accompanied by epidermal hyperplasia. The injection of testosterone into the ear also produced

Jonathan R. Matias; Norman Orentreich

1983-01-01

370

The future of recombinant growth factors in wound healing  

Microsoft Academic Search

For more than a decade, clinical trials have been conducted of the application of topical exogenous recombinant growth factors in attempts to accelerate the healing of chronic wounds. Although the results of some of these trials have been encouraging, overall the results have been somewhat discouraging. Much of the difficulty lies in the paucity of carefully controlled clinical trials of

Martin C. Robson; Thomas A. Mustoe; Thomas K. Hunt

1998-01-01

371

ARTICLE IN PRESS Platelet-derived growth factor regulates oligodendrocyte  

E-print Network

ARTICLE IN PRESS Platelet-derived growth factor regulates oligodendrocyte progenitor numbers such as multiple sclerosis, it will be important to understand the mechanisms that control oligodendrocyte­xxx sclerosis (MS) (Franklin, 2002; Ludwin, 1987). A major source of remyelinating oligodendrocytes is thought

Richardson, William D.

372

Fibroblast Growth Factor-2 Alters the Nature of Extinction  

ERIC Educational Resources Information Center

These experiments examined the effects of the NMDA-receptor (NMDAr) antagonist MK801 on reacquisition and re-extinction of a conditioned fear that had been previously extinguished before injection of fibroblast growth factor-2 (FGF2) or vehicle. Recent findings have shown that relearning and re-extinction, unlike initial learning and extinction,…

Graham, Bronwyn M.; Richardson, Rick

2011-01-01

373

Controlled growth factor release from synthetic extracellular matrices  

NASA Astrophysics Data System (ADS)

Polymeric matrices can be used to grow new tissues and organs, and the delivery of growth factors from these matrices is one method to regenerate tissues. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels, is that most drug delivery systems have been designed to operate under static conditions. We thought that polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments. Critical design features for this type of system include the ability to undergo repeated deformation, and a reversible binding of the protein growth factors to polymeric matrices to allow for responses to repeated stimuli. Here we report a model delivery system that can respond to mechanical signalling and upregulate the release of a growth factor to promote blood vessel formation. This approach may find a number of applications, including regeneration and engineering of new tissues and more general drug-delivery applications.

Lee, Kuen Yong; Peters, Martin C.; Anderson, Kenneth W.; Mooney, David J.

2000-12-01

374

Platelet-derived growth factor in chemotactic for fibroblasts  

Microsoft Academic Search

Chemotaxis assays in modified Boyden chambers were used to detect fibroblast chemoat- tractants in materials released from early-stage inflammatory cells, namely, mast cells, platelets, and neutrophils . Strong attractant activity was found in substances released from platelets . This activity was accounted for mainly by the platelet-derived growth factor (PDGF), which is released from the platelets and which was active

HEIKKI SEPPA; GARY GROTENDORST; SILJA SEPPA; ELLIOTT SCHIFFMANN; GEORGE R. MARTIN

1982-01-01

375

Nerve growth factor levels and localisation in human asthmatic bronchi  

Microsoft Academic Search

Nerve growth factor (NGF) has recently been suggested to be an important mediator of inflammation. In support of this, serum levels of NGF have been shown to be enhanced in asthmatics. However, it has not yet been shown whether the levels of NGF are also altered locally in asthmatic airways, when compared with healthy subjects, and the localisation of potential

C. Olgart Hoglund; F. de Blay; J. P. Oster; C. Duvernelle; O. Kassel; G. Pauli; N. Frossard

2002-01-01

376

Fibroblast growth factor signalling: from development to cancer  

Microsoft Academic Search

Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents

Nicholas Turner; Richard Grose

2010-01-01

377

Role of vascular endothelial growth factor in diabetic vascular complications  

Microsoft Academic Search

Role of vascular endothelial growth factor in diabetic vascular complicationsBackgroundMuch of the morbidity and mortality associated with diabetes mellitus predominantly reflects its deleterious effects on microcirculation and macrocirculation. During the past few years, rapid advancement has been made in our understanding of the mechanisms and molecules involved in the pathogenesis of diabetic microvasculopathy. This is particularly true with regard to

Lloyd Paul Aiello; Jun-Shyan Wong

2000-01-01

378

The role of growth factors in preimplantation development  

Microsoft Academic Search

It has become clear that the mammalian embryo participates in a complex dialogue with the maternal physiology. The language of the dialogue is growth factor signalling. The embryo expresses receptors for insulin, IGFs, GH, EGF and cytokines including LIF, and CSFs; whilst ligands are secreted by the supporting tissues of the oviduct and uterus, and in some cases, the embryo

Peter L. Kaye; Mark B. Harveyt

1995-01-01

379

Preimplantation embryo development enhanced by epidermal growth factor  

Microsoft Academic Search

Purpose: Enhanced embryo maturity and advanced stages of cleavage at the time of embryo transfer are associated with superior pregnancy rates in in vitro fertilization procedures. This study was performed to assess the potential usefulness of epid#rmal growth factor (EGF) to enhance the development of murine preimplantation embryos cultured in vitro. Two-cell stage mouse embryos were cultured for 72 hr

Richard P. Buyalos; Xuanqing Cai

1994-01-01

380

Constitution of Fibrin-Based Niche for In Vitro Differentiation of Adipose-Derived Mesenchymal Stem Cells to Keratinocytes  

PubMed Central

Abstract Epithelialization of chronic cutaneous wound is troublesome and may require use of skin/cell substitutes. Adipose-derived mesenchymal stem cells (ADMSCs) have immense potential as autologous cell source for treating wounds; they can cross the germ layer boundary of differentiation and regenerate skin. When multipotent adult stem cells are considered for skin regeneration, lineage committed keratinocytes may be beneficial to prevent undesirable post-transplantation outcome. This study hypothesized that ADMSCs may be directed to epidermal lineage in vitro on a specifically designed biomimetic and biodegradable niche. Cells were seeded on the test niche constituted with fibrin, fibronectin, gelatin, hyaluronic acid, laminin V, platelet growth factor, and epidermal growth factor in the presence of cell-specific differentiation medium (DM). The ADMSCs grown on bare tissue culture polystyrene surface in DM is designated DM-control and those grown in basal medium (BM) is the BM-control. Lineage commitment was monitored with keratinocyte-specific markers such as cytokeratin 14, cytokeratin 5, cytokeratin 19, and integrin ?6 at the transcriptional/translational level. The in vitro designed biomimetic fibrin composite matrix may have potential application as cell transplantation vehicle. PMID:25469318

Sivan, Unnikrishnan; Jayakumar, K.

2014-01-01

381

COW PLACENTA EXTRACT PROMOTES MURINE HAIR GROWTH THROUGH ENHANCING THE INSULIN - LIKE GROWTH FACTOR-1  

PubMed Central

Background: Hair loss is seen as an irreversible process. Most research concentrates on how to elongate the anagen, reduce the negative factors of obstructing hair growth and improve the hair number and size. Aim: In our experiment, we tried to prove that the cow placenta extract can promote hair growth by elongating hair shaft and increasing hair follicle number. Materials and Methods: Cow placenta extract (CPE), water and minoxidil applied separately on the back of depilated B57CL/6 mice for the case, negative and positive control respectively. We checked the proliferation of cells which are resident in hair sheath, and the expression of a few growth factors which stimulate hair growth. Results: Result shows that placenta extract more efficiently accelerates cell division and growth factor expression, by raising the insulin-like growth factor (IGF-1) mRNA and protein level to increase HF size and hair length. Conclusions: The extract is not a purified product; so, it is less effective than minoxidil, which is approved by the US FDA for the treatment of male pattern baldness. If refinement is done, the placenta extract would be a good candidate medicine for hair loss. PMID:21572784

Zhang, Dongliang; Lijuan, Gu; Jingjie, Li; Zheng, Li; Wang, Chunyan; Wang, Zhen; Liu, Lei; Mira, Li; Sung, Changkeun

2011-01-01

382

Fibroblast Growth Factors Stimulate Hair Growth through ?-Catenin and Shh Expression in C57BL/6 Mice  

PubMed Central

Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric analysis data indicates that topical application of FGFs induced an earlier anagen phase and prolonged the mature anagen phase, in contrast to the control group. Moreover, the immunohistochemical analysis reveals earlier induction of ?-catenin and Sonic hedgehog (Shh) in hair follicles of the FGFs-treated group. These results suggest that FGFs promote hair growth by inducing the anagen phase in resting hair follicles and might be a potential hair growth-promoting agent. PMID:25685806

Lin, Wei-hong; Xiang, Li-Jun; Shi, Hong-Xue; Zhang, Jian; Jiang, Li-ping; Cai, Ping-tao; Lin, Zhen-Lang; Lin, Bei-Bei; Huang, Yan; Zhang, Hai-Lin; Fu, Xiao-Bing; Guo, Ding-Jiong; Li, Xiao-Kun; Wang, Xiao-Jie; Xiao, Jian

2015-01-01

383

Expression of an Exogenous Growth Hormone Gene by Transplantable Human Epidermal Cells  

Microsoft Academic Search

Retrovirus-mediated gene transfer was used to introduce a recombinant human growth hormone gene into cultured human keratinocytes. The transduced keratinocytes secreted biologically active growth hormone into the culture medium. When grafted as an epithelial sheet onto athymic mice, these cultured keratinocytes reconstituted an epidermis that was similar in appearance to that resulting from normal cells, but from which human growth

Jeffrey R. Morgan; Yann Barrandon; Howard Green; Richard C. Mulligan

1987-01-01

384

Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors  

Microsoft Academic Search

The primary structure of the receptor for platelet-derived growth factor (PDGF), determined by means of cloning a cDNA that encodes the murine pre-PDGF receptor, is closely related to that of the v-kit oncogene product and the receptor for macrophage colony stimulating factor (CSF-1). Common structural features include the presence of long sequences that interrupt the tyrosine-specific protein kinase domains of

Y. Yarden; J. A. Escobedo; W.-J. Kuang; T. L. Yang-Feng; T. O. Daniel; P. M. Tremble; E. Y. Chen; M. E. Ando; R. N. Harkins; U. Francke; V. A. Fried; A. Ullrich; L. T. Williams

1986-01-01

385

Secretion of Extracellular Matrix (Fibronectin), Growth Factor (Transforming Growth Factor ?) and Protease (Cathepsin D) by Hepatoma Cells  

Microsoft Academic Search

We investigated facilitation of invasion by growth factors and chemotactic factors in tumor cell lines, particularly hepatocellular carcinoma. Hepatoma cells (PLC\\/PRF\\/5 and Hep G2) showed strong chemotaxis toward their respective conditioned media while metastatic pancreatic cancer cells (SU.86.86) and colon cancer cells (LS 174T) did not migrate toward their respective conditioned media. Based on immunoblotting, PLC\\/PRF\\/5 cells secrete fibronectin (an

Hiroshi Ito; Masaru Miyazaki; Fusanori Nishimura; Nobuyuki Nakajima

2000-01-01

386

Rat prostatic growth factors: purification and characterization of high and low molecular weight epidermal growth factors from rat dorsolateral prostate.  

PubMed

Growth factors which possibly participate in androgen-induced proliferation of rat prostate epithelial cells have been purified and characterized. Four distinct forms of growth factor were found in the extract of rat dorsolateral prostate. One of the factors was a member of heparin-binding growth factor (HBGF) family judging from its high affinity for heparin-Sepharose. The other three factors were capable of competing with [125I]epidermal growth factor (EGF) for the cell surface receptor, and recognized by anti-rat EGF antiserum. These EGF-like factors (EGF1-EGF3) were purified by ion-exchange chromatography, gel filtration and reverse phase HPLC. EGF1 showed microheterogeneity on chromatographic and electrophoretic separation and N-terminal sequence analysis. EGF1 showed an average molecular weight of about 35,000 on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. These results indicated that EGF1 was a mixture of high molecular weight forms of EGF. The molecular weights of EGF2 and EGF3 were similar to that of rat submaxillary gland EGF (Mr = 5400). The amino acid sequence of EGF2 was identical with that of rat EGF except for the N- and C-terminal amino acids: aspartic acid instead of asparagine was found at the N-terminal position and C-terminal arginine was missing in EGF2. Although the N-terminal sequence of EGF3 (1-19) was identical with that of EGF2, the two factors were completely separated by gel filtration indicating a difference in the C-terminal structure. EGF1, EGF2 and EGF3 but not HBGF stimulated proliferation of primary cultured rat dorsolateral prostate epithelial cells. PMID:1958699

Nishi, N; Shimizu, C; Okutani, T; Kagawa, Y; Takasuga, H; Suno, M; Wada, F

1991-11-12

387

VIP and Growth Factors in the Infected Cornea  

PubMed Central

Purpose. Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide that downregulates proinflammatory cytokines and promotes healing in a susceptible model of P. aeruginosa keratitis. Growth factors also play a role in corneal healing and restoration of tissue homeostasis after wounding. However, whether VIP treatment modulates growth factors to promote healing in the infected cornea remains untested and is the purpose of this study. Methods. C57BL/6 (B6) mice were injected with VIP and mRNA and protein levels, and immunostaining for EGF, FGF, HGF, and VEGF-A were done. Exogenous treatment with a mixture of the growth factors also was tested and levels of cytokines, defensins, and bacterial counts were determined. Results. Real-time RT-PCR, immunostaining, and ELISA data demonstrated that treatment with VIP enhanced levels of EGF, FGF, and HGF during disease, and that VEGF-A, and associated angiogenic molecules also were increased by VIP. Moreover, immunohistochemical studies confirmed that both epithelial and stromal cells participated in growth factor production. Most notably, treatment with a mixture of EGF, FGF, and HGF after disease onset, prevented corneal perforation when compared with controls. This outcome was associated with downregulation of proinflammatory cytokines such as macrophage inflammatory protein-2 (MIP-2), upregulation of anti-inflammatory cytokines such as TGF-?, and antimicrobials ?-defensins 2 and 3, as well as decreased plate counts at 1 day postinfection (p.i.) (P = 0.0001). Conclusions. Collectively, the data provide evidence that VIP treatment modulates growth factors, angiogenic molecules, and defensins in the infected cornea and that this in turn promotes healing and restoration of tissue homeostasis. PMID:21666233

Jiang, Xiaoyu; McClellan, Sharon A.; Barrett, Ronald P.; Berger, Elizabeth A.; Zhang, Yunfan

2011-01-01

388

Overexpression of Vascular Permeability Factor\\/Vascular Endothelial Growth Factor and its Receptors in Psoriasis  

Microsoft Academic Search

Summary Psoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and fit-l, are overexpressed by papillary dermal

Michael Detmar; Lawrence F. Brown; Kevin P. Claffey; Kiang-Teck Yeo; Olivier Kocher; Robert W. Jackman; Brygida Berse; Harold F. Dvorak

1994-01-01

389

Vascular Endothelial growth factor signaling in hypoxia and Inflammation  

PubMed Central

Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by reprogramming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions. PMID:24610033

Ramakrishnan, S.; Anand, Vidhu; Roy, Sabita

2014-01-01

390

Induction of nerve growth factor receptors on cultured human melanocytes  

SciTech Connect

Normal differentiation and malignant transformation of human melanocytes involve a complex series of interactions during which both genetic and environmental factors play roles. At present, the regulation of these processes is poorly understood. The authors have induced the expression of nerve growth factor (NGF) receptors on cultured human melanocytes with phorbol 12-tetradecanoate 13-acetate and have correlated this event with the appearance of a more differentiated, dendritic morphology. Criteria for NGF receptor expression included protein accumulation and cell-surface immunofluorescent staining with a monoclonal antibody directed against the human receptor and induction of the messenger RNA species as determined by blot-hybridization studies. The presence of the receptor could also be induced by UV irradiation or growth factor deprivation. The NGF receptor is inducible in cultured human melanocytes, and they suggest that NGF may modulate the behavior of this neural crest-derived cell in the skin.

Peacocke, M.; Yaar, M.; Mansur, C.P.; Chao, M.V.; Gilchrest, B.A. (Tufts Univ., Boston, MA (USA))

1988-07-01

391

20-O-?-D-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginsenoside Rb1, enhances the production of hyaluronic acid through the activation of ERK and Akt mediated by Src tyrosin kinase in human keratinocytes.  

PubMed

The aim of the present study was to determine the mechanisms through which 20-O-?-D-glucopyranosyl-20(S)-protopanaxadiol (20GPPD) promotes the production of hyaluronic acid (HA) in human keratinocytes. 20GPPD is the primary bioactive metabolite of Rb1, a major ginsenoside found in ginseng (Panax ginseng). We sought to elucidate the underlying mechanisms behind the 20GPPD-induced production of HA. We found that 20GPPD induced an increase in HA production by elevating hyaluronan synthase 2 (HAS2) expression in human keratinocytes. The phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was also enhanced by 20GPPD in a dose-dependent manner. The pharmacological inhibition of ERK (using U0126) or Akt (using LY294002) suppressed the 20GPPD-induced expression of HAS2, whereas treatment with an epidermal growth factor receptor (EGFR) inhibitor (AG1478) or an intracellular Ca2+ chelator (BAPTA/AM) did not exert any observable effects. The increased Src phosphorylation was also confirmed following treatment with 20GPPD in the human keratinocytes. Following pre-treatment with the Src inhibitor, PP2, both HA production and HAS2 expression were attenuated. Furthermore, the 20GPPD-enhanced ERK and Akt signaling decreased following treatment with PP2. Taken together, our results suggest that Src kinase plays a critical role in the 20GPPD-induced production of HA by acting as an upstream modulator of ERK and Akt activity in human keratinocytes. PMID:25738334

Lim, Tae-Gyu; Jeon, Ae Ji; Yoon, Ji Hye; Song, Dasom; Kim, Jong-Eun; Kwon, Jung Yeon; Kim, Jong Rhan; Kang, Nam Joo; Park, Jun-Seong; Yeom, Myeong Hun; Oh, Deok-Kun; Lim, Yoongho; Lee, Charles C; Lee, Chang Yong; Lee, Ki Won

2015-05-01

392

Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.  

PubMed Central

VPF/VEGF is a multifunctional cytokine that contributes to angiogenesis by both direct and indirect mechanisms. On the one hand, VPF/VEGF stimulates the ECs lining nearby microvessels to proliferate, to migrate, and to alter their pattern of gene expression. On the other hand, VPF/VEGF renders these same microvascular ECs hyperpermeable so that they spill plasma proteins into the extravascular space, leading to the clotting of extravasated fibrinogen with deposition of a fibrin gel. Extravascular fibrin serves as a provisional matrix that favors and supports the ingrowth of new blood vessels and other mesenchymal cells that generate mature, vascularized stroma. These same principles apply in tumors, in several examples of non-neoplastic pathology, and in physiological processes that involve angiogenesis and new stroma generation. In all of these examples, microvascular hyperpermeability and the introduction of a provisional, plasma-derived matrix precede and accompany the onset of EC division and new blood vessel formation. It would seem, therefore, that tumors have "borrowed" fundamental mechanisms that developed in multicellular organisms for purposes of tissue defense, renewal, and repair. VPF/VEGF, therefore has taught us something new about angiogenesis; namely, that vascular hyperpermeability and consequent plasma protein extravasation are important, perhaps essential, elements in its generation. However, this finding raises a paradox. While VPF/VEGF induces vascular hyperpermeability, other potent angiogenic factors apparently do not, at least in subtoxic concentrations that are more than sufficient to induce angiogenesis. Nonetheless, wherever angiogenesis has been studied, the newly generated vessels have been found to be hyperpermeable. How, therefore, do angiogenic factors other than VPF/VEGF lead to the formation of new and leaky blood vessels? We do not as yet have a complete answer to this question. One possibility is that at least some angiogenic factors mediate their effect by inducing or stimulating the expression of VPF/VEGF. In fact, there is already one clear example of this. TGF-alpha is a potent angiogenic factor but does not itself increase microvascular permeability. However, TGF-alpha strikingly upregulates VPF/VEGF expression in cultured keratinocytes and is thought to be responsible, at least in part, for the overexpression of VPF/VEGF in psoriasis. Moreover, overexpression of TGF-alpha, along with that of the EGF receptor with which it interacts, is characteristic of many malignant tumors, raising the possibility that TGF-alpha acts to stimulate VPF/VEGF expression in other types of epithelial cells and in this manner induces angiogenesis.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7538264

Dvorak, H. F.; Brown, L. F.; Detmar, M.; Dvorak, A. M.

1995-01-01

393

The effect of a levonorgestrel-releasing intrauterine system on angiogenic growth factors in the endometrium  

Microsoft Academic Search

BACKGROUND: The study aim was to investigate the effects of a levonorgestrel-releasing intrauterine system (LNG-IUS) on the secretion profiles and level of mRNA transcripts for angiogenic growth factors including vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-b1, basic fibroblast growth factor (bFGF) and endothelial growth factor (EGF) in the endometrium, and their levels in plasma. METHODS: Blood and endo-

B. A. Roopa; Annamalai Loganath; Kuldip Singh

2003-01-01

394

Inhibition of Transcription Factor Specificity Protein 1 Alters the Gene Expression Profile of Keratinocytes Leading to Upregulation of Kallikrein-Related Peptidases and Thymic Stromal Lymphopoietin  

Microsoft Academic Search

Transcription factor specificity protein 1 (Sp1) is involved in diverse cellular functions. We recently found that Sp1 was significantly decreased in skin biopsy samples obtained from patients with atopic dermatitis (AD) and had an even greater reduction in AD patients with a history of eczema herpeticum. In the current study, we sought to better understand the role of Sp1 in

Lianghua Bin; Byung E Kim; Clifton F Hall; Sonia M Leach; Donald Y M Leung

2011-01-01

395

Differential Response of Human Adipose Tissue-Derived Mesenchymal Stem Cells, Dermal Fibroblasts, and Keratinocytes to Burn Wound Exudates: Potential Role of Skin-Specific Chemokine CCL27  

PubMed Central

Many cell-based regenerative medicine strategies toward tissue-engineered constructs are currently being explored. Cell–cell interactions and interactions with different biomaterials are extensively investigated, whereas very few studies address how cultured cells will interact with soluble wound-healing mediators that are present within the wound bed after transplantation. The aim of this study was to determine how adipose tissue-derived mesenchymal stem cells (ASC), dermal fibroblasts, and keratinocytes will react when they come in contact with the deep cutaneous burn wound bed. Burn wound exudates isolated from deep burn wounds were found to contain many cytokines, including chemokines and growth factors related to inflammation and wound healing. Seventeen mediators were identified by ELISA (concentration range 0.0006–9?ng/mg total protein), including the skin-specific chemokine CCL27. Burn wound exudates activated both ASC and dermal fibroblasts, but not keratinocytes, to increase secretion of CXCL1, CXCL8, CCL2, and CCL20. Notably, ASC but not fibroblasts or keratinocytes showed significant increased secretion of vascular endothelial growth factor (5-fold) and interleukin-6 (253-fold), although when the cells were incorporated in bi-layered skin substitute (SS) these differences were less pronounced. A similar discrepancy between ASC and dermal fibroblast mono-cultures was observed when recombinant human-CCL27 was used instead of burn wound exudates. Although CCL27 did not stimulate the secretion of any of the wound-healing mediators by keratinocytes, these cells, in contrast to ASC or dermal fibroblasts, showed increased proliferation and migration. Taken together, the