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Sample records for luminal signal target

  1. The relative contributions of colour and luminance signals towards the visuomotor localisation of targets in human peripheral vision.

    PubMed

    Ashida, Hiroshi; Yamagishi, Noriko; Anderson, Stephen J

    2007-12-01

    We sought to determine the extent to which colour (and luminance) signals contribute towards the visuomotor localization of targets. To do so we exploited the movement-related illusory displacement a small stationary window undergoes when it has a continuously moving carrier grating behind it. We used drifting (1.0-4.2 Hz) red/green-modulated isoluminant gratings or yellow/black luminance-modulated gratings as carriers, each curtailed in space by a stationary, two-dimensional window. After each trial, the perceived location of the window was recorded with reference to an on-screen ruler (perceptual task) or the on-screen touch of a ballistic pointing movement made without visual feedback (visuomotor task). Our results showed that the perceptual displacement measures were similar for each stimulus type and weakly dependent on stimulus drift rate. However, while the visuomotor displacement measures were similar for each stimulus type at low drift rates (<4 Hz), they were significantly larger for luminance than colour stimuli at high drift rates (>4 Hz). We show that the latter cannot be attributed to differences in perceived speed between stimulus types. We assume, therefore, that our visuomotor localization judgements were more susceptible to the (carrier) motion of luminance patterns than colour patterns. We suggest that, far from being detrimental, this susceptibility may indicate the operation of mechanisms designed to counter the temporal asynchrony between perceptual experiences and the physical changes in the environment that give rise to them. We propose that perceptual localisation is equally supported by both colour and luminance signals but that visuomotor localisation is predominantly supported by luminance signals. We discuss the neural pathways that may be involved with visuomotor localization. PMID:17643232

  2. Luminance and chromatic contributions to a hyperacuity task: isolation by contrast polarity and target separation

    PubMed Central

    Sun, Hao; Cooper, Bonnie; Lee, Barry B.

    2012-01-01

    Vernier thresholds are known to be elevated when a target pair has opposite contrast polarity. Polarity reversal is used to assess the role of luminance and chromatic pathways in hyperacuity performance. Psychophysical hyperacuity thresholds were measured for pairs of gratings of various combinations of luminance (Lum) and chromatic (Chr) contrast polarities, at different ratios of luminance to chromatic contrast. With two red-green gratings of matched luminance and chromatic polarity (+Lum+Chr), there was an elevation of threshold at isoluminance. When both luminance and chromatic polarity were mismatched (−Lum−Chr), thresholds were substantially elevated under all conditions. With the same luminance contrast polarity and opposite chromatic polarity (+Lum−Chr) thresholds were only elevated close to isoluminance; in the reverse condition (−Lum+Chr), thresholds were elevated as in the −Lum−Chr condition except close to equiluminance. Similar data were obtained for gratings isolating the short-wavelength cone mechanism. Further psychophysical measurements assessed the role of target separation with matched or mismatched contrast polarity; similar results were found for luminance and chromatic gratings. Comparison physiological data were collected from parafoveal ganglion cells of the macaque retina. Positional precision of ganglion cell signals was assessed under conditions related to the psychophysical measurements. On the basis of these combined observations, it is argued that both magnocellular, parvocellular, and koniocellular pathways have access to cortical positional mechanisms associated with vernier acuity. PMID:22306680

  3. Luminal Ca(2+) dynamics during IP3R mediated signals.

    PubMed

    Lopez, Lucia F; Dawson, Silvina Ponce

    2016-01-01

    The role of cytosolic Ca(2+) on the kinetics of Inositol 1,4,5-triphosphate receptors (IP3Rs) and on the dynamics of IP3R-mediated Ca(2+) signals has been studied at large both experimentally and by modeling. The role of luminal Ca(2+) has not been investigated with that much detail although it has been found that it is relevant for signal termination in the case of Ca(2+) release through ryanodine receptors. In this work we present the results of observing the dynamics of luminal and cytosolic Ca(2+) simultaneously in Xenopus laevis oocytes. Combining observations and modeling we conclude that there is a rapid mechanism that guarantees the availability of free Ca(2+) in the lumen even when a relatively large Ca(2+) release is evoked. Comparing the dynamics of cytosolic and luminal Ca(2+) during a release, we estimate that they are consistent with a 80% of luminal Ca(2+) being buffered. The rapid availability of free luminal Ca(2+) correlates with the observation that the lumen occupies a considerable volume in several regions across the images. PMID:27232767

  4. Luminal Ca2+ dynamics during IP3R mediated signals

    NASA Astrophysics Data System (ADS)

    Lopez, Lucia F.; Ponce Dawson, Silvina

    2016-06-01

    The role of cytosolic Ca2+ on the kinetics of Inositol 1,4,5-triphosphate receptors (IP3Rs) and on the dynamics of IP3R-mediated Ca2+ signals has been studied at large both experimentally and by modeling. The role of luminal Ca2+ has not been investigated with that much detail although it has been found that it is relevant for signal termination in the case of Ca2+ release through ryanodine receptors. In this work we present the results of observing the dynamics of luminal and cytosolic Ca2+ simultaneously in Xenopus laevis oocytes. Combining observations and modeling we conclude that there is a rapid mechanism that guarantees the availability of free Ca2+ in the lumen even when a relatively large Ca2+ release is evoked. Comparing the dynamics of cytosolic and luminal Ca2+ during a release, we estimate that they are consistent with a 80% of luminal Ca2+ being buffered. The rapid availability of free luminal Ca2+ correlates with the observation that the lumen occupies a considerable volume in several regions across the images.

  5. The impact of target luminance and radiance on night vision device visual performance testing

    NASA Astrophysics Data System (ADS)

    Marasco, Peter L.; Task, H. Lee

    2003-09-01

    Visual performance through night-vision devices (NVDs) is a function of many parameters such as target contrast, objective and eyepiece lens focus, signal/noise of the image intensifier tube, quality of the image intensifier, night-vision goggle (NVG) gain, and NVG output luminance to the eye. The NVG output luminance depends on the NVG sensitive radiance emitted (or reflected) from the visual acuity target (usually a vision testing chart). The primary topic of this paper is the standardization (or lack thereof) of the radiance levels used for NVG visual acuity testing. The visual acuity chart light level might be determined in either photometric (luminance) units or radiometric (radiance) units. The light levels are often described as "starlight," "quarter moon," or "optimum" light levels and may not actually provide any quantitative photometric or radiometric information. While these terms may be useful to pilots and the users of night-vision devices, they are inadequate for accurate visual performance testing. This is because there is no widely accepted agreement in the night vision community as to the radiance or luminance level of the target that corresponds to the various named light levels. This paper examines the range of values for "starlight," "quarter moon," and "optimum" light commonly used by the night vision community and referenced in the literature. The impact on performance testing of variations in target luminance/radiance levels is also examined. Arguments for standardizing on NVG-weighted radiometric units for testing night-vision devices instead of photometric units are presented. In addition, the differences between theoretical weighted radiance and actual weighted radiance are also discussed.

  6. A Leak Pathway for Luminal Protons in Endosomes Drives Oncogenic Signaling in Glioblastoma

    PubMed Central

    Kondapalli, Kalyan C.; Llongueras, Jose P.; Capilla-González, Vivian; Prasad, Hari; Hack, Anniesha; Smith, Christopher; Guerrero-Cázares, Hugo; Quiñones-Hinojosa, Alfredo; Rao, Rajini

    2015-01-01

    Epidermal growth factor receptor (EGFR) signaling is a potent driver of glioblastoma, a malignant and lethal form of brain cancer. Disappointingly, inhibitors targeting receptor tyrosine kinase activity are not clinically effective, and EGFR persists on the plasma membrane to maintain tumor growth and invasiveness. Here we show that endolysosomal pH is critical for receptor sorting and turnover. By functioning as a leak pathway for protons, the Na+/H+ exchanger NHE9 limits luminal acidification to circumvent EGFR turnover and prolong downstream signaling pathways that drive tumor growth and migration. In glioblastoma, NHE9 expression is associated with stem/progenitor characteristics, radiochemoresistance, poor prognosis and invasive growth in vitro and in vivo. Silencing or inhibition of NHE9 in brain tumor initiating cells attenuates tumorsphere formation and improves efficacy of EGFR inhibitor. Thus, NHE9 mediates inside-out control of oncogenic signaling and is a highly druggable target for pan-specific receptor clearance in cancer therapy. PMID:25662504

  7. Segregation of chromatic and luminance signals using a novel grating stimulus.

    PubMed

    Lee, Barry B; Sun, Hao; Valberg, Arne

    2011-01-01

    Segregation of chromatic and luminance signals in afferent pathways are investigated with a grating stimulus containing luminance and chromatic components of different spatial frequencies. Ganglion cell recordings were obtained from the retinae of macaques (Macaca fascicularis). Cell responses to the 'compound' gratings were compared to responses to standard chromatic and luminance gratings. Parvocellular (PC) pathway cell responses to compound and chromatic gratings were very similar, as were magnocellular (MC) cell responses to compound and luminance gratings. This was the case over a broad range of spatial and temporal frequencies and contrasts. In psychophysical experiments with human observers, discrimination between grating types was possible close to detection threshold. These results are consistent with chromatic and luminance structure in complex patterns being strictly localized in different afferent pathways. This novel stimulus may prove useful in identifying afferent inputs to cortical neurons. PMID:20937716

  8. Segregation of chromatic and luminance signals using a novel grating stimulus

    PubMed Central

    Lee, Barry B; Sun, Hao; Valberg, Arne

    2011-01-01

    Segregation of chromatic and luminance signals in afferent pathways are investigated with a grating stimulus containing luminance and chromatic components of different spatial frequencies. Ganglion cell recordings were obtained from the retinae of macaques (Macaca fascicularis). Cell responses to the ‘compound’ gratings were compared to responses to standard chromatic and luminance gratings. Parvocellular (PC) pathway cell responses to compound and chromatic gratings were very similar, as were magnocellular (MC) cell responses to compound and luminance gratings. This was the case over a broad range of spatial and temporal frequencies and contrasts. In psychophysical experiments with human observers, discrimination between grating types was possible close to detection threshold. These results are consistent with chromatic and luminance structure in complex patterns being strictly localized in different afferent pathways. This novel stimulus may prove useful in identifying afferent inputs to cortical neurons. PMID:20937716

  9. Combining S-cone and luminance signals adversely affects discrimination of objects within backgrounds

    PubMed Central

    Jennings, Ben J.; Tsattalios, Konstantinos; Chakravarthi, Ramakrishna; Martinovic, Jasna

    2016-01-01

    The visual system processes objects embedded in complex scenes that vary in both luminance and colour. In such scenes, colour contributes to the segmentation of objects from backgrounds, but does it also affect perceptual organisation of object contours which are already defined by luminance signals, or are these processes unaffected by colour’s presence? We investigated if luminance and chromatic signals comparably sustain processing of objects embedded in backgrounds, by varying contrast along the luminance dimension and along the two cone-opponent colour directions. In the first experiment thresholds for object/non-object discrimination of Gaborised shapes were obtained in the presence and absence of background clutter. Contrast of the component Gabors was modulated along single colour/luminance dimensions or co-modulated along multiple dimensions simultaneously. Background clutter elevated discrimination thresholds only for combined S-(L + M) and L + M signals. The second experiment replicated and extended this finding by demonstrating that the effect was dependent on the presence of relatively high S-(L + M) contrast. These results indicate that S-(L + M) signals impair spatial vision when combined with luminance. Since S-(L + M) signals are characterised by relatively large receptive fields, this is likely to be due to an increase in the size of the integration field over which contour-defining information is summed. PMID:26856308

  10. A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma.

    PubMed

    Kondapalli, Kalyan C; Llongueras, Jose P; Capilla-González, Vivian; Prasad, Hari; Hack, Anniesha; Smith, Christopher; Guerrero-Cázares, Hugo; Quiñones-Hinojosa, Alfredo; Rao, Rajini

    2015-01-01

    Epidermal growth factor receptor (EGFR) signalling is a potent driver of glioblastoma, a malignant and lethal form of brain cancer. Disappointingly, inhibitors targeting receptor tyrosine kinase activity are not clinically effective and EGFR persists on the plasma membrane to maintain tumour growth and invasiveness. Here we show that endolysosomal pH is critical for receptor sorting and turnover. By functioning as a leak pathway for protons, the Na(+)/H(+) exchanger NHE9 limits luminal acidification to circumvent EGFR turnover and prolong downstream signalling pathways that drive tumour growth and migration. In glioblastoma, NHE9 expression is associated with stem/progenitor characteristics, radiochemoresistance, poor prognosis and invasive growth in vitro and in vivo. Silencing or inhibition of NHE9 in brain tumour-initiating cells attenuates tumoursphere formation and improves efficacy of EGFR inhibitor. Thus, NHE9 mediates inside-out control of oncogenic signalling and is a highly druggable target for pan-specific receptor clearance in cancer therapy. PMID:25662504

  11. The SDSS-IV Extended Baryon Oscillation Spectroscopic Survey: Luminous Red Galaxy Target Selection

    NASA Astrophysics Data System (ADS)

    Prakash, Abhishek; Licquia, Timothy C.; Newman, Jeffrey A.; Ross, Ashley J.; Myers, Adam D.; Dawson, Kyle S.; Kneib, Jean-Paul; Percival, Will J.; Bautista, Julian E.; Comparat, Johan; Tinker, Jeremy L.; Schlegel, David J.; Tojeiro, Rita; Ho, Shirley; Lang, Dustin; Rao, Sandhya M.; McBride, Cameron K.; Ben Zhu, Guangtun; Brownstein, Joel R.; Bailey, Stephen; Bolton, Adam S.; Delubac, Timothée; Mariappan, Vivek; Blanton, Michael R.; Reid, Beth; Schneider, Donald P.; Seo, Hee-Jong; Carnero Rosell, Aurelio; Prada, Francisco

    2016-06-01

    We describe the algorithm used to select the luminous red galaxy (LRG) sample for the extended Baryon Oscillation Spectroscopic Survey (eBOSS) of the Sloan Digital Sky Survey IV (SDSS-IV) using photometric data from both the SDSS and the Wide-field Infrared Survey Explorer. LRG targets are required to meet a set of color selection criteria and have z-band and i-band MODEL magnitudes z < 19.95 and 19.9 < i < 21.8, respectively. Our algorithm selects roughly 50 LRG targets per square degree, the great majority of which lie in the redshift range 0.6 < z < 1.0 (median redshift 0.71). We demonstrate that our methods are highly effective at eliminating stellar contamination and lower-redshift galaxies. We perform a number of tests using spectroscopic data from SDSS-III/BOSS ancillary programs to determine the redshift reliability of our target selection and its ability to meet the science requirements of eBOSS. The SDSS spectra are of high enough signal-to-noise ratio that at least ∼89% of the target sample yields secure redshift measurements. We also present tests of the uniformity and homogeneity of the sample, demonstrating that it should be clean enough for studies of the large-scale structure of the universe at higher redshifts than SDSS-III/BOSS LRGs reached.

  12. The SDSS-IV Extended Baryon Oscillation Spectroscopic Survey: Luminous Red Galaxy Target Selection

    NASA Astrophysics Data System (ADS)

    Prakash, Abhishek; Licquia, Timothy C.; Newman, Jeffrey A.; Ross, Ashley J.; Myers, Adam D.; Dawson, Kyle S.; Kneib, Jean-Paul; Percival, Will J.; Bautista, Julian E.; Comparat, Johan; Tinker, Jeremy L.; Schlegel, David J.; Tojeiro, Rita; Ho, Shirley; Lang, Dustin; Rao, Sandhya M.; McBride, Cameron K.; Ben Zhu, Guangtun; Brownstein, Joel R.; Bailey, Stephen; Bolton, Adam S.; Delubac, Timothée; Mariappan, Vivek; Blanton, Michael R.; Reid, Beth; Schneider, Donald P.; Seo, Hee-Jong; Carnero Rosell, Aurelio; Prada, Francisco

    2016-06-01

    We describe the algorithm used to select the luminous red galaxy (LRG) sample for the extended Baryon Oscillation Spectroscopic Survey (eBOSS) of the Sloan Digital Sky Survey IV (SDSS-IV) using photometric data from both the SDSS and the Wide-field Infrared Survey Explorer. LRG targets are required to meet a set of color selection criteria and have z-band and i-band MODEL magnitudes z < 19.95 and 19.9 < i < 21.8, respectively. Our algorithm selects roughly 50 LRG targets per square degree, the great majority of which lie in the redshift range 0.6 < z < 1.0 (median redshift 0.71). We demonstrate that our methods are highly effective at eliminating stellar contamination and lower-redshift galaxies. We perform a number of tests using spectroscopic data from SDSS-III/BOSS ancillary programs to determine the redshift reliability of our target selection and its ability to meet the science requirements of eBOSS. The SDSS spectra are of high enough signal-to-noise ratio that at least ˜89% of the target sample yields secure redshift measurements. We also present tests of the uniformity and homogeneity of the sample, demonstrating that it should be clean enough for studies of the large-scale structure of the universe at higher redshifts than SDSS-III/BOSS LRGs reached.

  13. On the necessity of correcting peripheral target luminance for pupillary area

    SciTech Connect

    Bedell, H.E.; Katz, L.M.

    1982-10-01

    Despite the decrease in pupillary area for peripheral targets, retinal illuminance remains fairly constant to about 80 deg visual angle. Constant illuminance is maintained in the retinal periphery because the light that enters the pupil is concentrated into smaller retinal images. The correction of the peripheral target luminances for pupillary area is therefore unnecessary except under certain conditions.

  14. Basal but not luminal mammary epithelial cells require PI3K/mTOR signaling for Ras-driven overgrowth.

    PubMed

    Plichta, Kristin A; Mathers, Jessica L; Gestl, Shelley A; Glick, Adam B; Gunther, Edward J

    2012-11-15

    The mammary ducts of humans and mice are comprised of two main mammary epithelial cell (MEC) subtypes: a surrounding layer of basal MECs and an inner layer of luminal MECs. Breast cancer subtypes show divergent clinical behavior that may reflect properties inherent in their MEC compartment of origin. How the response to a cancer-initiating genetic event is shaped by MEC subtype remains largely unexplored. Using the mouse mammary gland, we designed organotypic three-dimensional culture models that permit challenge of discrete MEC compartments with the same oncogenic insult. Mammary organoids were prepared from mice engineered for compartment-restricted coexpression of oncogenic H-RAS(G12V) together with a nuclear fluorescent reporter. Monitoring of H-RAS(G12V)-expressing MECs during extended live cell imaging permitted visualization of Ras-driven phenotypes via video microscopy. Challenging either basal or luminal MECs with H-RAS(G12V) drove MEC proliferation and survival, culminating in aberrant organoid overgrowth. In each compartment, Ras activation triggered modes of collective MEC migration and invasion that contrasted with physiologic modes used during growth factor-initiated branching morphogenesis. Although basal and luminal Ras activation produced similar overgrowth phenotypes, inhibitor studies revealed divergent use of Ras effector pathways. Blocking either the phosphoinositide 3-kinase or the mammalian target of rapamycin pathway completely suppressed Ras-driven invasion and overgrowth of basal MECs, but only modestly attenuated Ras-driven phenotypes in luminal MECs. We show that MEC subtype defines signaling pathway dependencies downstream of Ras. Thus, cells-of-origin may critically determine the drug sensitivity profiles of mammary neoplasia. PMID:23010075

  15. Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling

    PubMed Central

    Carrara, Marta; Prischi, Filippo; Nowak, Piotr R; Ali, Maruf MU

    2015-01-01

    Stress caused by accumulation of misfolded proteins within the endoplasmic reticulum (ER) elicits a cellular unfolded protein response (UPR) aimed at maintaining protein-folding capacity. PERK, a key upstream component, recognizes ER stress via its luminal sensor/transducer domain, but the molecular events that lead to UPR activation remain unclear. Here, we describe the crystal structures of mammalian PERK luminal domains captured in dimeric state as well as in a novel tetrameric state. Small angle X-ray scattering analysis (SAXS) supports the existence of both crystal structures also in solution. The salient feature of the tetramer interface, a helix swapped between dimers, implies transient association. Moreover, interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. PMID:25925385

  16. Parafoveal Target Detectability Reversal Predicted by Local Luminance and Contrast Gain Control

    NASA Technical Reports Server (NTRS)

    Ahumada, Albert J., Jr.; Beard, Bettina L.; Null, Cynthia H. (Technical Monitor)

    1996-01-01

    This project is part of a program to develop image discrimination models for the prediction of the detectability of objects in a range of backgrounds. We wanted to see if the models could predict parafoveal object detection as well as they predict detection in foveal vision. We also wanted to make our simplified models more general by local computation of luminance and contrast gain control. A signal image (0.78 x 0.17 deg) was made by subtracting a simulated airport runway scene background image (2.7 deg square) from the same scene containing an obstructing aircraft. Signal visibility contrast thresholds were measured in a fully crossed factorial design with three factors: eccentricity (0 deg or 4 deg), background (uniform or runway scene background), and fixed-pattern white noise contrast (0%, 5%, or 10%). Three experienced observers responded to three repetitions of 60 2IFC trials in each condition and thresholds were estimated by maximum likelihood probit analysis. In the fovea the average detection contrast threshold was 4 dB lower for the runway background than for the uniform background, but in the parafovea, the average threshold was 6 dB higher for the runway background than for the uniform background. This interaction was similar across the different noise levels and for all three observers. A likely reason for the runway background giving a lower threshold in the fovea is the low luminance near the signal in that scene. In our model, the local luminance computation is controlled by a spatial spread parameter. When this parameter and a corresponding parameter for the spatial spread of contrast gain were increased for the parafoveal predictions, the model predicts the interaction of background with eccentricity.

  17. Colonic luminal surface retention of meloxicam microsponges delivered by erosion based colon-targeted matrix tablet.

    PubMed

    Srivastava, Rishabh; Kumar, Deepesh; Pathak, Kamla

    2012-05-10

    The work was aimed at developing calcium-pectinate matrix tablet for colon-targeted delivery of meloxicam (MLX) microsponges. Modified quassi-emulsion solvent diffusion method was used to formulate microsponges (MS), based on 3(2) full factorial design. The effects of volume of dichloromethane and EudragitRS100 content (independent variables) were determined on the particle size, entrapment efficiency and %cumulative drug release of MS1-MS9. The optimized formulation, MS5 (d(mean)=44.47 μm, %EE=98.73, %CDR=97.32 and followed zero order release) was developed into colon-targeted matrix tablet using calcium pectinate as the matrix. The optimized colon-targeted tablet (MS5T2) shielded MLX loaded microsponges in gastrointestinal region and selectively delivered them to colon, as vizualized by vivo fluoroscopy in rabbits. The pharmacokinetic evaluation of MS5T2 in rabbits, revealed appearance of drug appeared in plasma after a lag time of 7h; a t(max) of 30 h with Fr=61.047%, thus presenting a formulation suitable for targeted colonic delivery. CLSM studies provided an evidence for colonic luminal retentive ability of microsponges at the end of 8h upon oral administration of MS5T2. Thus calcium pectinate matrix tablet loaded with MLX microsponges was developed as a promising system for the colon-specific delivery that has potential for use as an adjuvant therapy for colorectal cancer. PMID:22306039

  18. miR-221/222 control luminal breast cancer tumor progression by regulating different targets

    PubMed Central

    Dentelli, Patrizia; Traversa, Matteo; Rosso, Arturo; Togliatto, Gabriele; Olgasi, Cristina; Marchiò, Caterina; Provero, Paolo; Lembo, Antonio; Bon, Giulia; Annaratone, Laura; Sapino, Anna; Falcioni, Rita; Brizzi, Maria Felice

    2014-01-01

    α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3′UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted “normal” breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy. PMID:24736554

  19. The Presence of VEGF Receptors on the Luminal Surface of Endothelial Cells Affects VEGF Distribution and VEGF Signaling

    PubMed Central

    Stefanini, Marianne O.; Wu, Florence T. H.; Mac Gabhann, Feilim; Popel, Aleksander S.

    2009-01-01

    Vascular endothelial growth factor (VEGF) is a potent cytokine that binds to specific receptors on the endothelial cells lining blood vessels. The signaling cascade triggered eventually leads to the formation of new capillaries, a process called angiogenesis. Distributions of VEGF receptors and VEGF ligands are therefore crucial determinants of angiogenic events and, to our knowledge, no quantification of abluminal vs. luminal receptors has been performed. We formulate a molecular-based compartment model to investigate the VEGF distribution in blood and tissue in humans and show that such quantification would lead to new insights on angiogenesis and VEGF-dependent diseases. Our multiscale model includes two major isoforms of VEGF (VEGF121 and VEGF165), as well as their receptors (VEGFR1 and VEGFR2) and the non-signaling co-receptor neuropilin-1 (NRP1). VEGF can be transported between tissue and blood via transendothelial permeability and the lymphatics. VEGF receptors are located on both the luminal and abluminal sides of the endothelial cells. In this study, we analyze the effects of the VEGF receptor localization on the endothelial cells as well as of the lymphatic transport. We show that the VEGF distribution is affected by the luminal receptor density. We predict that the receptor signaling occurs mostly on the abluminal endothelial surface, assuming that VEGF is secreted by parenchymal cells. However, for a low abluminal but high luminal receptor density, VEGF binds predominantly to VEGFR1 on the abluminal surface and VEGFR2 on the luminal surface. Such findings would be pertinent to pathological conditions and therapies related to VEGF receptor imbalance and overexpression on the endothelial cells and will hopefully encourage experimental receptor quantification for both luminal and abluminal surfaces on endothelial cells. PMID:20041209

  20. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha

    SciTech Connect

    Hua, Wei; Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing; Yang, An-Gang; Zhang, Rui; Fan, Jing; Bian, Ka

    2015-08-07

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3’-untranslated region (3′UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. - Highlights: • High levels of TOP2a expression are closely associated with poor prognosis in luminal type breast cancer patients. • TOP2a is a novel target of miR-139. • Overexpression of miR-139 inhibits proliferation in luminal type breast cancer cells. • TOP2a is essential for miR-139-induced growth arrest in luminal type breast cancer cells.

  1. The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis.

    PubMed

    Flemban, Arwa; Qualtrough, David

    2015-01-01

    The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT. PMID:26389956

  2. Separate visual signals for saccade initiation during target selection in the primate superior colliculus.

    PubMed

    White, Brian J; Munoz, Douglas P

    2011-02-01

    The primary function of the superior colliculus (SC) is to orient the visual system toward behaviorally relevant stimuli defined by features such as color. However, a longstanding view has held that visual activity in the SC arises exclusively from achromatic pathways. Recently, we reported evidence that the primate SC is highly sensitive to signals originating from chromatic pathways, but these signals are delayed relative to luminance signals (White et al., 2009). Here, we describe a functional consequence of this difference in visual arrival time on the processes leading to target selection and saccade initiation. Two rhesus monkeys performed a simple color-singleton selection task in which stimuli carried a chromatic component only (target and distractors were isoluminant with the background, but differed in chromaticity) or a combined chromatic-achromatic component (36% luminance contrast added equally to all stimuli). Although visual responses were delayed in the chromatic-only relative to the combined chromatic-achromatic condition, SC neurons discriminated the target from distractors at approximately the same time provided stimulus chromaticity was held constant. However, saccades were triggered sooner, and with more errors, with the chromatic-achromatic condition, suggesting that luminance signals associated with these stimuli increased the probability of triggering a saccade before the target color was adequately discriminated. These results suggest that separate mechanisms may independently influence the saccadic command in the SC, one linked to the arrival time of pertinent visual signals, and another linked to the output of the visual selection process. PMID:21289164

  3. Micro RNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR

    PubMed Central

    He, Yuan; Fu, Xing; Fu, Liya; Zhu, Zhengmao; Fu, Li; Dong, Jin-Tang

    2016-01-01

    Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment. PMID:26744318

  4. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha.

    PubMed

    Hua, Wei; Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing; Yang, An-Gang; Zhang, Rui; Fan, Jing; Bian, Ka

    2015-08-01

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3'-untranslated region (3'UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. PMID:26079880

  5. Targeting Notch Signaling in Colorectal Cancer

    PubMed Central

    Suman, Suman; Das, Trinath P.; Ankem, Murali K.; Damodaran, Chendil

    2014-01-01

    The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC), hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer. PMID:25395896

  6. Targeting Notch Signaling in Colorectal Cancer.

    PubMed

    Suman, Suman; Das, Trinath P; Ankem, Murali K; Damodaran, Chendil

    2014-12-01

    The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC), hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer. PMID:25395896

  7. Advances in Targeting Signal Transduction Pathways

    PubMed Central

    McCubrey, James A.; Steelman, Linda S.; Chappell, William H.; Sun, Lin; Davis, Nicole M.; Abrams, Stephen L.; Franklin, Richard A.; Cocco, Lucio; Evangelisti, Camilla; Chiarini, Francesca; Martelli, Alberto M.; Libra, Massimo; Candido, Saverio; Ligresti, Giovanni; Malaponte, Grazia; Mazzarino, Maria C.; Fagone, Paolo; Donia, Marco; Nicoletti, Ferdinando; Polesel, Jerry; Talamini, Renato; Bäsecke, Jörg; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela; Milella, Michele; Tafuri, Agostino; Dulińska-Litewka, Joanna; Laidler, Piotr; D'Assoro, Antonio B.; Drobot, Lyudmyla; Umezawa, Kazuo; Montalto, Giuseppe; Cervello, Melchiorre; Demidenko, Zoya N.

    2012-01-01

    Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies. PMID:23455493

  8. Prolactin-induced prostate tumorigenesis links sustained Stat5 signaling with the amplification of basal/stem cells and emergence of putative luminal progenitors.

    PubMed

    Sackmann-Sala, Lucila; Chiche, Aurélie; Mosquera-Garrote, Nerea; Boutillon, Florence; Cordier, Corinne; Pourmir, Ivan; Pascual-Mathey, Luz; Kessal, Karima; Pigat, Natascha; Camparo, Philippe; Goffin, Vincent

    2014-11-01

    Current androgen ablation therapies for prostate cancer are initially successful, but the frequent development of castration resistance urges the generation of alternative therapies and represents an important health concern. Prolactin/signal transducer and activator of transcription 5 (STAT5) signaling is emerging as a putative target for alternative treatment for prostate cancer. However, mechanistic data for its role in development or progression of prostate tumors are scarce. In vivo mouse studies found that local prolactin induced the amplification of prostate epithelial basal/stem cells. Because these cells are proposed cells of origin for prostate cancer and disease recurrence, we looked further into this amplification. Our results indicated that sustained Stat5 activation was associated with the occurrence of abnormal basal/stem cell clusters in prostate epithelium of prostate-specific prolactin-transgenic mice. Analysis of epithelial areas containing these clusters found high proliferation, Stat5 activation, and expression of stem cell antigen 1. Furthermore, enhanced prolactin signaling also led to amplification of a luminal cell population that was positive for stem cell antigen 1. These cells may originate from amplified basal/stem cells and might represent important progenitors for tumor development in prostate epithelium. These data provide a deeper understanding of the initial stages of prostate tumorigenesis induced by prolactin to help determine whether this hormone or its downstream messengers could be useful targets for prostate cancer treatment in the future. PMID:25193592

  9. Duodenal luminal nutrient sensing

    PubMed Central

    Rønnestad, Ivar; Akiba, Yasutada; Kaji, Izumi; Kaunitz, Jonathan D

    2016-01-01

    The gastrointestinal mucosa is exposed to numerous chemical substances and microorganisms, including macronutrients, micronutrients, bacteria, endogenous ions, and proteins. The regulation of mucosal protection, digestion, absorption and motility is signaled in part by luminal solutes. Therefore, luminal chemosensing is an important mechanism enabling the mucosa to monitor luminal conditions, such as pH, ion concentrations, nutrient quantity, and microflora. The duodenal mucosa shares luminal nutrient receptors with lingual taste receptors in order to detect the five basic tastes, in addition to essential nutrients, and unwanted chemicals. The recent ‘de-orphanization’ of nutrient sensing G protein-coupled receptors provides an essential component of the mechanism by which the mucosa senses luminal nutrients. In this review, we will update the mechanisms of and underlying physiological and pathological roles in luminal nutrient sensing, with a main focus on the duodenal mucosa. PMID:25113991

  10. A MAP OF THE INTEGRATED SACHS-WOLFE SIGNAL FROM LUMINOUS RED GALAXIES

    SciTech Connect

    Granett, Benjamin R.; Neyrinck, Mark C.; Szapudi, Istvan

    2009-08-10

    We construct a map of the time derivative of the gravitational potential traced by Sloan Digital Sky Survey luminous red galaxies (LRGs). The potential decays on large scales due to cosmic acceleration, leaving an imprint on cosmic microwave background (CMB) radiation through the integrated Sachs-Wolfe (ISW) effect. With a template fit, we directly measure this signature on the CMB at a 2{sigma} confidence level. The measurement is consistent with the cross-correlation statistic, strengthening the claim that dark energy is indeed the cause of the correlation. This new approach potentially simplifies the cosmological interpretation. Our constructed linear ISW map shows no evidence for degree-scale cold and hot spots associated with supervoid and supercluster structures. This suggests that the linear ISW effect in a concordance {lambda}CDM cosmology is insufficient to explain the strong CMB imprints from these structures that we previously reported.

  11. Targeting Signaling Transduction Pathways in Bladder Cancer.

    PubMed

    Abbosh, Phillip H; McConkey, David J; Plimack, Elizabeth R

    2015-12-01

    Systemic therapy for urothelial carcinoma (UC) of the bladder has largely revolved around cytotoxic chemotherapy regimens. However, several recent clinical trials have explored the roles of targeted therapies which specifically inhibit signal transduction pathways. Simultaneously, a rationale for such therapies has come to the forefront of management of this disease because an overabundance of signaling pathways are genetically deranged as a result of point mutation or copy number alteration (CNA) as identified by several recent next generation sequencing (NGS) studies. Importantly, these derangements are found in all stages of disease, and therefore targeted therapies hold promise as a next step in the evolution of the medical management of both localized and metastatic UCC. We review the rationale for and progress in studying inhibition of signal transduction as a means of treatment of UCC. PMID:26472299

  12. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    PubMed Central

    Fulda, Simone

    2011-01-01

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner. PMID:22655234

  13. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation

    PubMed Central

    Choi, Nahyun; Zhang, Boyu; Zhang, Li; Ittmann, Michael; Xin, Li

    2012-01-01

    Summary The prostate epithelial lineage hierarchy and the cellular origin for prostate cancer remain inadequately defined. Using a lineage tracing approach, we show that adult rodent prostate basal and luminal cells are independently self-sustained in vivo. Disrupting the tumor suppressor Pten in either lineage led to prostate cancer initiation. However, the cellular composition and onset dynamics of the resulting tumors are distinctive. Prostate luminal cells are more responsive to Pten null-induced mitogenic signaling. In contrast, basal cells are resistant to direct transformation. Instead, loss of Pten activity induces the capability of basal cells to differentiate into transformation-competent luminal cells. Our study suggests that deregulation of epithelial differentiation is a critical step for the initiation of prostate cancers of basal cell origin. PMID:22340597

  14. Targeting TGF-β signaling in cancer

    PubMed Central

    Katz, Lior H; Li, Ying; Chen, Jiun-Sheng; Muñoz, Nina M; Majumdar, Avijit; Chen, Jian; Mishra, Lopa

    2013-01-01

    Introduction The transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β pathway are crucial in developing TGF-β-based therapeutics for cancer. Areas covered This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given. Expert opinion Targeting the TGF-β pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-β and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-β in each specific tumor. Future studies are needed in order to find safer and more effective TGF-β-based drugs. PMID:23651053

  15. Targets of light signalling in Trichoderma reesei

    PubMed Central

    2013-01-01

    Background The tropical ascomycete Trichoderma reesei (Hypocrea jecorina) represents one of the most efficient plant cell wall degraders. Regulation of the enzymes required for this process is affected by nutritional signals as well as other environmental signals including light. Results Our transcriptome analysis of strains lacking the photoreceptors BLR1 and BLR2 as well as ENV1 revealed a considerable increase in the number of genes showing significantly different transcript levels in light and darkness compared to wild-type. We show that members of all glycoside hydrolase families can be subject to light dependent regulation, hence confirming nutrient utilization including plant cell wall degradation as a major output pathway of light signalling. In contrast to N. crassa, photoreceptor mediated regulation of carbon metabolism in T. reesei occurs primarily by BLR1 and BLR2 via their positive effect on induction of env1 transcription, rather than by a presumed negative effect of ENV1 on the function of the BLR complex. Nevertheless, genes consistently regulated by photoreceptors in N. crassa and T. reesei are significantly enriched in carbon metabolic functions. Hence, different regulatory mechanisms are operative in these two fungi, while the light dependent regulation of plant cell wall degradation appears to be conserved. Analysis of growth on different carbon sources revealed that the oxidoreductive D-galactose and pentose catabolism is influenced by light and ENV1. Transcriptional regulation of the target enzymes in these pathways is enhanced by light and influenced by ENV1, BLR1 and/or BLR2. Additionally we detected an ENV1-regulated genomic cluster of 9 genes including the D-mannitol dehydrogenase gene lxr1, with two genes of this cluster showing consistent regulation in N. crassa. Conclusions We show that one major output pathway of light signalling in Trichoderma reesei is regulation of glycoside hydrolase genes and the degradation of hemicellulose

  16. Targeting oncogenic Ras signaling in hematologic malignancies

    PubMed Central

    Ward, Ashley F.; Braun, Benjamin S.

    2012-01-01

    Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼ 25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer. PMID:22898602

  17. Targeting RTK Signaling Pathways in Cancer

    PubMed Central

    Regad, Tarik

    2015-01-01

    The RAS/MAP kinase and the RAS/PI3K/AKT pathways play a key role in the regulation of proliferation, differentiation and survival. The induction of these pathways depends on Receptor Tyrosine Kinases (RTKs) that are activated upon ligand binding. In cancer, constitutive and aberrant activations of components of those pathways result in increased proliferation, survival and metastasis. For instance, mutations affecting RTKs, Ras, B-Raf, PI3K and AKT are common in perpetuating the malignancy of several types of cancers and from different tissue origins. Therefore, these signaling pathways became prime targets for cancer therapy. This review aims to provide an overview about the most frequently encountered mutations, the pathogenesis that results from such mutations and the known therapeutic strategies developed to counteract their aberrant functions. PMID:26404379

  18. Wideband radar signal modeling of ground moving targets in clutter

    NASA Astrophysics Data System (ADS)

    Malas, John A.; Pasala, Krishna M.; Westerkamp, John J.

    2002-08-01

    Research in the area of air-to-ground target detection, track and identification (ID) requires the development of target signal models for known geometric shapes moving in ground clutter. Space-time adaptive filtering techniques in particular make good use of temporal-spatial synthetic radar signal return data. A radar signal model is developed to generate synthetic wideband radar signal data for use in multi-channel adaptive signal processing.

  19. Klf5 Deletion Promotes Pten Deletion–Initiated Luminal-Type Mouse Prostate Tumors through Multiple Oncogenic Signaling Pathways12

    PubMed Central

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N.; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-01-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer—mutation/deletion of Pten and deletion of Klf5. PMID:25425963

  20. Targeting NRF2 signaling for cancer chemoprevention

    SciTech Connect

    Kwak, Mi-Kyoung; Kensler, Thomas W.

    2010-04-01

    Modulation of the metabolism and disposition of carcinogens through induction of cytoprotective enzymes is one of several promising strategies to prevent cancer. Chemopreventive efficacies of inducers such as dithiolethiones and sulforaphane have been extensively studied in animals as well as in humans. The KEAP1-NRF2 system is a key, but not unilateral, molecular target for these chemopreventive agents. The transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of the expression of a subset of genes, which produce proteins responsible for the detoxication of electrophiles and reactive oxygen species as well as the removal or repair of some of their damage products. It is believed that chemopreventive enzyme inducers affect the interaction between KEAP1 and NRF2 through either mediating conformational changes of the KEAP1 protein or activating phosphorylation cascades targeting the KEAP1-NRF2 complex. These events in turn affect NRF2 stability and trafficking. Recent advances elucidating the underlying structural biology of KEAP1-NRF2 signaling and identification of the gene clusters under the transcriptional control of NRF2 are facilitating understanding of the potential pleiotropic effects of NRF2 activators and discovery of novel classes of potent chemopreventive agents such as the triterpenoids. Although there is appropriately a concern regarding a deleterious role of the KEAP1-NRF2 system in cancer cell biology, especially as the pathway affects cell survival and drug resistance, the development and the use of NRF2 activators as chemopreventive agents still holds a great promise for protection of normal cells from a diversity of environmental stresses that contribute to the burden of cancer and other chronic, degenerative diseases.

  1. Superoxide targets calcineurin signaling in vascular endothelium

    SciTech Connect

    Namgaladze, Dmitry . E-mail: dmitry@zbc.kgu.de; Shcherbyna, Ivanna; Kienhoefer, Joachim; Hofer, H. Werner; Ullrich, Volker

    2005-09-09

    Superoxide emerges as key regulatory molecule in many aspects of vascular physiology and disease, but identification of superoxide targets in the vasculature remains elusive. In this work, we investigated the possibility of inhibition of protein phosphatase calcineurin by superoxide in endothelial cells. We employed a redox cycler 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) to generate superoxide inside the cells. DMNQ caused inhibition of cellular calcineurin phosphatase activity, which was reversible upon DMNQ removal. Inhibition was suppressed by pre-incubating the cells with copper/zinc superoxide dismutase (Cu,ZnSOD). In addition, reducing cellular Cu,ZnSOD activity by diethylthiocarbamic acid treatment resulted in calcineurin inhibition and enhanced sensitivity to DMNQ. Further, we could show that DMNQ inhibits calcineurin-dependent nuclear translocation and transcriptional activation of NFAT transcription factor, and Cu,ZnSOD or superoxide scavenger Tiron reduced the inhibition. Thus, superoxide generation in endothelial cells results in inhibition of calcineurin signaling, which could have important pathophysiological implications in the vasculature.

  2. Epidermal growth factor: Porcine uterine luminal epithelial cell migratory signal during the peri-implantation period of pregnancy.

    PubMed

    Jeong, Wooyoung; Jung, Seoungo; Bazer, Fuller W; Song, Gwonhwa; Kim, Jinyoung

    2016-01-15

    The majority of early conceptus mortality in pregnancy occurs during the peri-implantation period, suggesting that this period is important for conceptus viability and the establishment of pregnancy. Successful establishment of pregnancy in all mammalian species depends on the orchestrated molecular events that transpire at the conceptus-uterine interface during the peri-implantation period of pregnancy. This maternal-conceptus interaction is especially crucial in pigs because they have a non-invasive epitheliochorial placentation during a protracted peri-implantation period. During the pre-implantation period of pregnancy, conceptus survival and the establishment of pregnancy depend on the developing conceptus receiving an adequate supply of histotroph which contains a wide range of nutrients and growth factors. Evidence links epidermal growth factor (EGF) to embryogenesis or implantation in various mammalian species. EGF exhibits potential growth-promoting activities on the conceptus and endometrium; however, in the case of pigs, little is known its functions, especially their regulatory mechanisms at the maternal-conceptus interface. EGF receptor (EGFR) mRNA and protein are abundant in endometrial luminal (LE) and glandular (GE) epithelia and conceptus trophectoderm on Days 13-14 of pregnancy, suggesting that EGF provides an autocrine signal to uterine LE and GE just prior to implantation. Therefore, the objectives of this study were to determine: 1) the potential intracellular signaling pathways responsible for the activities of EGF in porcine uterine LE (pLE) cells; and 2) the changes in cellular activities induced by EGF. EGF treatment of pLE cells increased the abundance of phosphorylated (p)-ERK1/2, p-P70RSK and p-RPS6 compared to that for control cells. Furthermore, EGF-stimulated phosphorylation of ERK1/2 MAPK was inhibited in pLE cells transfected with an EGFR siRNA compared with control siRNA-transfected pLE cells. Moreover, EGF stimulated migration of

  3. Luminal cholinergic signalling in airway lining fluid: a novel mechanism for activating chloride secretion via Ca2+-dependent Cl− and K+ channels

    PubMed Central

    Hollenhorst, Monika I; Lips, Katrin S; Wolff, Miriam; Wess, Jürgen; Gerbig, Stefanie; Takats, Zoltan; Kummer, Wolfgang; Fronius, Martin

    2012-01-01

    BACKGROUND AND PURPOSE Recent studies detected the expression of proteins involved in cholinergic metabolism in airway epithelial cells, although the function of this non-neuronal cholinergic system is not known in detail. Thus, this study focused on the effect of luminal ACh as a regulator of transepithelial ion transport in epithelial cells. EXPERIMENTAL APPROACH RT-PCR experiments were performed using mouse tracheal epithelial cells for ChAT and organic cation transporter (OCT) transcripts. Components of tracheal airway lining fluid were analysed with desorption electrospray ionization (DESI) MS. Effects of nicotine on mouse tracheal epithelial ion transport were examined with Ussing-chamber experiments. KEY RESULTS Transcripts encoding ChAT and OCT1–3 were detected in mouse tracheal epithelial cells. The DESI experiments identified ACh in the airway lining fluid. Luminal ACh induced an immediate, dose-dependent increase in the transepithelial ion current (EC50: 23.3 µM), characterized by a transient peak and sustained plateau current. This response was not affected by the Na+-channel inhibitor amiloride. The Cl−-channel inhibitor niflumic acid or the K+-channel blocker Ba2+ attenuated the ACh effect. The calcium ionophore A23187 mimicked the ACh effect. Luminal nicotine or muscarine increased the ion current. Experiments with receptor gene-deficient animals revealed the participation of muscarinic receptor subtypes M1 and M3. CONCLUSIONS AND IMPLICATIONS The presence of luminal ACh and activation of transepithelial ion currents by luminal ACh receptors identifies a novel non-neuronal cholinergic pathway in the airway lining fluid. This pathway could represent a novel drug target in the airways. PMID:22300281

  4. TGF-β signaling and its targeting for glioma treatment

    PubMed Central

    Han, Jianfeng; Alvarez-Breckenridge, Christopher A; Wang, Qi-En; Yu, Jianhua

    2015-01-01

    Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine, secreted by a variety of cells including immune cells, tumor cells, and stromal cells. TGF-β signaling is dysregulated in cancer patients, and this aberrant signaling at least in part contributes to initiation and progression of many cancers including glioma. The dysregulated signaling components provide molecular targets for the treatment of glioma. In this article, we review TGF-β signaling and its targeting in glioma. PMID:26045979

  5. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling.

    PubMed Central

    García-Cardeña, G; Oh, P; Liu, J; Schnitzer, J E; Sessa, W C

    1996-01-01

    The membrane association of endothelial nitric oxide synthase (eNOS) plays an important role in the biosynthesis of nitric oxide (NO) in vascular endothelium. Previously, we have shown that in cultured endothelial cells and in intact blood vessels, eNOS is found primarily in the perinuclear region of the cells and in discrete regions of the plasma membrane, suggesting trafficking of the protein from the Golgi to specialized plasma membrane structures. Here, we show that eNOS is found in Triton X-100-insoluble membranes prepared from cultured bovine aortic endothelial cells and colocalizes with caveolin, a coat protein of caveolae, in cultured bovine lung microvascular endothelial cells as determined by confocal microscopy. To examine if eNOS is indeed in caveolae, we purified luminal endothelial cell plasma membranes and their caveolae directly from intact, perfused rat lungs. eNOS is found in the luminal plasma membranes and is markedly enriched in the purified caveolae. Because palmitoylation of eNOS does not significantly influence its membrane association, we next examined whether this modification can affect eNOS targeting to caveolae. Wild-type eNOS, but not the palmitoylation mutant form of the enzyme, colocalizes with caveolin on the cell surface in transfected NIH 3T3 cells, demonstrating that palmitoylation of eNOS is necessary for its targeting into caveolae. These data suggest that the subcellular targeting of eNOS to caveolae can restrict NO signaling to specific targets within a limited microenvironment at the cell surface and may influence signal transduction through caveolae. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8692835

  6. Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

    PubMed Central

    Tan, Antoinette R.; Alexe, Gabriela; Reiss, Michael

    2009-01-01

    In most human breast cancers, lowering of TGFβ receptor- or Smad gene expression combined with increased levels of TGFβs in the tumor microenvironment is sufficient to abrogate TGFβs tumor suppressive effects and to induce a mesenchymal, motile and invasive phenotype. In genetic mouse models, TGFβ signaling suppresses de novo mammary cancer formation but promotes metastasis of tumors that have broken through TGFβ tumor suppression. In mouse models of “triple-negative” or basal-like breast cancer, treatment with TGFβ neutralizing anti-bodies or receptor kinase inhibitors strongly inhibits development of lung- and bone metastases. These TGFβ antagonists do not significantly affect tumor cell proliferation or apoptosis. Rather, they de-repress anti-tumor immunity, inhibit angiogenesis and reverse the mesenchymal, motile, invasive phenotype characteristic of basal-like and HER2-positive breast cancer cells. Patterns of TGFβ target genes upregulation in human breast cancers suggest that TGFβ may drive tumor progression in estrogen-independent cancer, while it mediates a suppressive host cell response in estrogen-dependent luminal cancers. In addition, TGFβ appears to play a key role in maintaining the mammary epithelial (cancer) stem cell pool, in part by inducing a mesenchymal phenotype, while differentiated, estrogen receptor-positive, luminal cells are unresponsive to TGFβ because the TGFBR2 receptor gene is transcriptionally silent. These same cells respond to estrogen by downregulating TGFβ, while antiestrogens act by upregulating TGFβ. This model predicts that inhibiting TGFβ signaling should drive the differentiation of mammary stem cells into ductal cells. Consequently, TGFβ antagonists may convert basal-like or HER2-positive cancers to a more epithelioid, non-proliferating (and, perhaps, non-metastatic) phenotype. Conversely, these agents might antagonize the therapeutic effects of anti-estrogens in estrogen-dependent luminal cancers. These

  7. Targeting Signaling Pathways in Epithelial Ovarian Cancer

    PubMed Central

    Smolle, Elisabeth; Taucher, Valentin; Pichler, Martin; Petru, Edgar; Lax, Sigurd; Haybaeck, Johannes

    2013-01-01

    Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data In 2012, the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity. PMID:23644885

  8. Role of signal peptides in targeting of proteins in cyanobacteria.

    PubMed Central

    Mackle, M M; Zilinskas, B A

    1994-01-01

    Proteins of cyanobacteria may be transported across one of two membrane systems: the typical eubacterial cell envelope (consisting of an inner membrane, periplasmic space, and an outer membrane) and the photosynthetic thylakoids. To investigate the role of signal peptides in targeting in cyanobacteria, Synechococcus sp. strain PCC 7942 was transformed with vectors carrying the chloramphenicol acetyltransferase reporter gene fused to coding sequences for one of four different signal peptides. These included signal peptides of two proteins of periplasmic space origin (one from Escherichia coli and the other from Synechococcus sp. strain PCC 7942) and two other signal peptides of proteins located in the thylakoid lumen (one from a cyanobacterium and the other from a higher plant). The location of the gene fusion products expressed in Synechococcus sp. strain PCC 7942 was determined by a chloramphenicol acetyltransferase enzyme-linked immunosorbent assay of subcellular fractions. The distribution pattern for gene fusions with periplasmic signal peptides was different from that of gene fusions with thylakoid lumen signal peptides. Primary sequence analysis revealed conserved features in the thylakoid lumen signal peptides that were absent from the periplasmic signal peptides. These results suggest the importance of the signal peptide in protein targeting in cyanobacteria and point to the presence of signal peptide features conserved between chloroplasts and cyanobacteria for targeting of proteins to the thylakoid lumen. Images PMID:8144451

  9. Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened

    PubMed Central

    Gonnissen, Annelies; Isebaert, Sofie; Haustermans, Karin

    2015-01-01

    An essential role for Hedgehog (Hh) signaling in human cancer has been established beyond doubt. At present, targeting Hh signaling has mainly been investigated with SMO inhibitors. Unfortunately, resistance against currently used SMO inhibitors has already been observed in basal cell carcinoma (BCC) patients. Therefore, the use of Hh inhibitors targeting the signaling cascade more downstream of SMO could represent a more promising strategy. Furthermore, besides the classical canonical way of Hh signaling activation, non-canonical activation of the GLI transcription factors by multiple important signaling pathways (e.g. MAPK, PI3K, TGFβ) has also been described, pinpointing the importance of targeting the transcription factors GLI1/2. The most promising agent in this context is probably the GLI1/2 inhibitor GANT61 which has been investigated preclinically in numerous tumor types in the last few years. In this review, the emerging role of Hh signaling in cancer is critically evaluated focusing on the potential of targeting Hh signaling more downstream of SMO, i.e. at the level of the GLI transcription factors. Furthermore, the working mechanism and therapeutic potential of the most extensively studied GLI inhibitor in human cancer, i.e. GANT61, is discussed in detail. In conclusion, GANT61 appears to be highly effective against human cancer cells and in xenograft mouse models, targeting almost all of the classical hallmarks of cancer and could hence represent a promising treatment option for human cancer. PMID:26053182

  10. Target image search using fMRI signals

    NASA Astrophysics Data System (ADS)

    Xiong, Shi; Song, Sutao; Zhan, Yu; Zhang, Jiacai

    2014-03-01

    Recent neural signal decoding studies based on functional magnetic resonance imaging (fMRI) have identified the specific image presenting to the subject from a set of potential images, and some studies extend neural decoding into image reconstruction, i.e. image contents that the subject perceived were decoded from the fMRI signals recorded during the subject looking at images. In this paper, we decoded the target images using fMRI signals and described a target image searching method based on the relationship between target image stimuli and fMRI activity. We recorded fMRI data during a serial visual stimuli image presentation task, some of the stimuli images were target images and the rest images were non-target ones. Our fMRI data analysis results showed that in the serial visual presentation task, target images elicited a stereotypical response in the fMRI, which can be detected by multi-voxel pattern analysis (MVPA). Classifiers designed with support vector machine (SVM) used this response to decipher target images from non-target images. The leave-one-run-out cross-validation showed that we can pick out the target images with a possibility far above the chance level, which indicate that there's a neural signatures correlated with the target image recognition process in the human systems.

  11. Luminous presence

    NASA Astrophysics Data System (ADS)

    Dawson, Paula

    2008-02-01

    The Luminous Presence project examines the use of standard film language in the framing, angle and of points of view of holographic subjects though eight digital holographic stereograms; seven 25 x 25 cm, Hail, Water, Rain, Snow, Sun, Text, Imprint and 1.5 x 1 m, Luminous Presences i. However, before embarking on a discussion of how filmic language can be used in digital holograms it is first important to explain why this line of investigation could be fruitful. Undoubtedly several of the compositional practices which sprung up and evolved throughout the development of the diverse forms of the holographic medium have contributed to a unique hologram pictorial language, however it is well known that the reading of visual imagery of any type relies a great deal on the viewer's knowledge of and experience of other images .The lens-recorded imagery of film is a far more familiar language than that of holograms and the correlation between certain filmic pictorial conventions and emotional responses are well documented and understood. ii . In short the language of film contains a highly nuanced vocabulary of shot types and lens types (which may be criticised as being formulaic) yet are effective in lending emotion to figures.

  12. Nonlinear photoacoustic signal amplification from single targets in absorption background☆

    PubMed Central

    Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Menyaev, Yulian A.; Juratli, Mazen A.; Zharov, Vladimir P.

    2013-01-01

    Photoacoustic (PA) detection of single absorbing targets such as nanoparticles or cells can be limited by absorption background. We show here that this problem can be overcome by using the nonlinear photoacoustics based on the differences in PA signal dependences on the laser energy from targets and background. Among different nonlinear phenomena, we focused on laser generation of nanobubbles as more efficient PA signal amplifiers from strongly absorbing, highly localized targets in the presence of spatially homogenous absorption background generating linear signals only. This approach was demonstrated by using nonlinear PA flow cytometry platform for label-free detection of circulating melanoma cells in blood background in vitro and in vivo. Nonlinearly amplified PA signals from overheated melanin nanoclusters in melanoma cells became detectable above still linear blood background. Nonlinear nanobubble-based photoacoustics provide new opportunities to significantly (5–20-fold) increase PA contrast of single nanoparticles, cells, viruses and bacteria in complex biological environments. PMID:24921062

  13. Nonlinear photoacoustic signal amplification from single targets in absorption background.

    PubMed

    Sarimollaoglu, Mustafa; Nedosekin, Dmitry A; Menyaev, Yulian A; Juratli, Mazen A; Zharov, Vladimir P

    2014-03-01

    Photoacoustic (PA) detection of single absorbing targets such as nanoparticles or cells can be limited by absorption background. We show here that this problem can be overcome by using the nonlinear photoacoustics based on the differences in PA signal dependences on the laser energy from targets and background. Among different nonlinear phenomena, we focused on laser generation of nanobubbles as more efficient PA signal amplifiers from strongly absorbing, highly localized targets in the presence of spatially homogenous absorption background generating linear signals only. This approach was demonstrated by using nonlinear PA flow cytometry platform for label-free detection of circulating melanoma cells in blood background in vitro and in vivo. Nonlinearly amplified PA signals from overheated melanin nanoclusters in melanoma cells became detectable above still linear blood background. Nonlinear nanobubble-based photoacoustics provide new opportunities to significantly (5-20-fold) increase PA contrast of single nanoparticles, cells, viruses and bacteria in complex biological environments. PMID:24921062

  14. Signal Transduction Molecules as Targets for Cancer Prevention

    PubMed Central

    Bode, Ann M.; Dong, Zigang

    2010-01-01

    Environmental and life-style aspects are major contributors to human carcinogenesis and, therefore, many human cancers may be preventable. Cancer is the end result of defects in cellular signaling processes that play a key role in the control of cell growth, survival, division, and differentiation. Therefore, identifying molecular and cellular targets critical in cancer development and prevention is an area of intensive research, driving the development of highly specific small-molecule inhibitors. A major idea today is that cancer may be prevented or treated by targeting the products of specific cancer-related genes, frequently encoding signaling proteins or transcription factors. Participants in these joint conferences discussed their latest findings in the identification of promising molecular targets and the development of agents directed against these targets with the goal of effectively transitioning these into the clinical setting. PMID:19244209

  15. Targeting PI3K/mTOR signaling in cancer.

    PubMed

    Emerling, Brooke M; Akcakanat, Argun

    2011-12-15

    The American Association for Cancer Research (AACR) Special Conference on Targeting PI3K/mTOR Signaling in Cancer was held in San Francisco, California from February 24 to 27, 2011. The meeting was cochaired by Drs. Lewis C. Cantley, David M. Sabatini, and Funda Meric-Bernstam. The main focus of this event was the therapeutic potential of drugs targeting the PI3K/mTOR signaling pathway for the treatment of cancer. This article summarizes the recent discoveries in the field, with particular emphasis on the major themes of the conference. PMID:21987725

  16. Targeting the PI3K signaling pathway in cancer

    PubMed Central

    Wong, Kwok-Kin; Engelman, Jeffrey A; Cantley, Lewis C

    2009-01-01

    The PI3K pathway is activated in a variety of different human cancers, and inhibitors of this pathway are under active development as anti-cancer therapeutics. In this review, we discuss the data supporting the use of PI3K pathway inhibitors in genetically and clinically defined cancers. This review focuses on their efficacy as single-agents and in combination with other targeted therapies, specifically those targeting the MEK-ERK signaling pathway. PMID:20006486

  17. Circumferential targeted renal sympathetic nerve denervation with preservation of the renal arterial wall using intra-luminal ultrasound

    NASA Astrophysics Data System (ADS)

    Roth, Austin; Coleman, Leslie; Sakakura, Kenichi; Ladich, Elena; Virmani, Renu

    2015-03-01

    An intra-luminal ultrasound catheter system (ReCor Medical's Paradise System) has been developed to provide circumferential denervation of the renal sympathetic nerves, while preserving the renal arterial intimal and medial layers, in order to treat hypertension. The Paradise System features a cylindrical non-focused ultrasound transducer centered within a balloon that circulates cooling fluid and that outputs a uniform circumferential energy pattern designed to ablate tissues located 1-6 mm from the arterial wall and protect tissues within 1 mm. RF power and cooling flow rate are controlled by the Paradise Generator which can energize transducers in the 8.5-9.5 MHz frequency range. Computer simulations and tissue-mimicking phantom models were used to develop the proper power, cooling flow rate and sonication duration settings to provide consistent tissue ablation for renal arteries ranging from 5-8 mm in diameter. The modulation of these three parameters allows for control over the near-field (border of lesion closest to arterial wall) and far-field (border of lesion farthest from arterial wall, consisting of the adventitial and peri-adventitial spaces) depths of the tissue lesion formed by the absorption of ultrasonic energy and conduction of heat. Porcine studies have confirmed the safety (protected intimal and medial layers) and effectiveness (ablation of 1-6 mm region) of the system and provided near-field and far-field depth data to correlate with bench and computer simulation models. The safety and effectiveness of the Paradise System, developed through computer model, bench and in vivo studies, has been demonstrated in human clinical studies.

  18. Signal Transduction in the Chronic Leukemias: Implications for Targeted Therapies

    PubMed Central

    Ahmed, Wesam; Van Etten, Richard A.

    2013-01-01

    The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways. PMID:23307472

  19. Cotranslational signal-independent SRP preloading during membrane targeting.

    PubMed

    Chartron, Justin W; Hunt, Katherine C L; Frydman, Judith

    2016-08-11

    Ribosome-associated factors must properly decode the limited information available in nascent polypeptides to direct them to their correct cellular fate. It is unclear how the low complexity information exposed by the nascent chain suffices for accurate recognition by the many factors competing for the limited surface near the ribosomal exit site. Questions remain even for the well-studied cotranslational targeting cycle to the endoplasmic reticulum, involving recognition of linear hydrophobic signal sequences or transmembrane domains by the signal recognition particle (SRP). Notably, the SRP has low abundance relative to the large number of ribosome-nascent-chain complexes (RNCs), yet it accurately selects those destined for the endoplasmic reticulum. Despite their overlapping specificities, the SRP and the cotranslationally acting Hsp70 display precise mutually exclusive selectivity in vivo for their cognate RNCs. To understand cotranslational nascent chain recognition in vivo, here we investigate the cotranslational membrane-targeting cycle using ribosome profiling in yeast cells coupled with biochemical fractionation of ribosome populations. We show that the SRP preferentially binds secretory RNCs before their targeting signals are translated. Non-coding mRNA elements can promote this signal-independent pre-recruitment of SRP. Our study defines the complex kinetic interaction between elongation in the cytosol and determinants in the polypeptide and mRNA that modulate SRP–substrate selection and membrane targeting. PMID:27487213

  20. Special issue: Proteoglycans: signaling, targeting and therapeutics: introduction.

    PubMed

    Karamanos, Nikos K; Linhardt, Robert J

    2013-05-01

    This special issue of FEBS Journal contains 31 review and primary research articles reflecting the advancements covered at the 2012 Proteoglycans Gordon Research Conference and novel aspects from experts in the field. It is mainly focused on current status of the extracellular and cell surface proteoglycans' regulatory roles in cell signaling, molecular targeting, engineering attempts and potential therapeutic approaches. PMID:23530537

  1. Progress in Small Molecule and Biologic Therapeutics Targeting Ghrelin Signaling.

    PubMed

    McGovern, Kayleigh R; Darling, Joseph E; Hougland, James L

    2016-01-01

    Ghrelin is a circulating peptide hormone involved in regulation of a wide array of physiological processes. As an endogenous ligand for growth hormone secretagogue receptor (GHSR1a), ghrelin is responsible for signaling involved in energy homeostasis, including appetite stimulation, glucose metabolism, insulin signaling, and adiposity. Ghrelin has also been implicated in modulation of several neurological processes. Dysregulation of ghrelin signaling is implicated in diseases related to these pathways, including obesity, type II diabetes, and regulation of appetite and body weight in patients with Prader-Willi syndrome. Multiple steps in the ghrelin signaling pathway are available for targeting in the development of therapeutics for these diseases. Agonists and antagonists of GHS-R1a have been widely studied and have shown varying levels of effectiveness within ghrelin-related physiological pathways. Agents targeting ghrelin directly, either through depletion of ghrelin levels in circulation or inhibitors of ghrelin O-acyltransferase whose action is required for ghrelin to become biologically active, are receiving increasing attention as potential therapeutic options. We discuss the approaches utilized to target ghrelin signaling and highlight the current challenges toward developing small-molecule agents as potential therapeutics for ghrelin-related diseases. PMID:26202202

  2. Resistance to targeted cancer drugs through hepatocyte growth factor signaling

    PubMed Central

    Heynen, Guus JJE; Fonfara, Aldona; Bernards, René

    2014-01-01

    Cancer therapeutics that target a signaling pathway to which the cancer cells are addicted can deliver dramatic initial responses, but resistance is nearly always inevitable. A variety of mechanisms that cancer cells employ to escape from targeted cancer drugs have been described. We review here the role of Hepatocyte Growth Factor (HGF) and its receptor MET in drug resistance. We present data demonstrating that HGF can confer resistance to a number of kinase inhibitors in a variety of cancer cell lines and discuss our results in relation to the findings of others. Together, these data point at a major role for HGF/MET signaling in resistance to a variety of targeted cancer drugs. PMID:25426675

  3. Activin signaling as an emerging target for therapeutic interventions

    PubMed Central

    Tsuchida, Kunihiro; Nakatani, Masashi; Hitachi, Keisuke; Uezumi, Akiyoshi; Sunada, Yoshihide; Ageta, Hiroshi; Inokuchi, Kaoru

    2009-01-01

    After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-β (TGF-β) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-β, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-β ligands, and control the signaling and availability of ligands. The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of

  4. Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1

    PubMed Central

    Ciani, Lorenza; Marzo, Aude; Boyle, Kieran; Stamatakou, Eleanna; Lopes, Douglas M.; Anane, Derek; McLeod, Faye; Rosso, Silvana B.; Gibb, Alasdair; Salinas, Patricia C.

    2015-01-01

    The functional assembly of the synaptic release machinery is well understood; however, how signalling factors modulate this process remains unknown. Recent studies suggest that Wnts play a role in presynaptic function. To examine the mechanisms involved, we investigated the interaction of release machinery proteins with Dishevelled-1 (Dvl1), a scaffold protein that determines the cellular locale of Wnt action. Here we show that Dvl1 directly interacts with Synaptotagmin-1 (Syt-1) and indirectly with the SNARE proteins SNAP25 and Syntaxin (Stx-1). Importantly, the interaction of Dvl1 with Syt-1, which is regulated by Wnts, modulates neurotransmitter release. Moreover, presynaptic terminals from Wnt signalling-deficient mice exhibit reduced release probability and are unable to sustain high-frequency release. Consistently, the readily releasable pool size and formation of SNARE complexes are reduced. Our studies demonstrate that Wnt signalling tunes neurotransmitter release and identify Syt-1 as a target for modulation by secreted signalling proteins. PMID:26400647

  5. Lidar Luminance Quantizer

    NASA Technical Reports Server (NTRS)

    Quilligan, Gerard; DeMonthier, Jeffrey; Suarez, George

    2011-01-01

    This innovation addresses challenges in lidar imaging, particularly with the detection scheme and the shapes of the detected signals. Ideally, the echoed pulse widths should be extremely narrow to resolve fine detail at high event rates. However, narrow pulses require wideband detection circuitry with increased power dissipation to minimize thermal noise. Filtering is also required to shape each received signal into a form suitable for processing by a constant fraction discriminator (CFD) followed by a time-to-digital converter (TDC). As the intervals between the echoes decrease, the finite bandwidth of the shaping circuits blends the pulses into an analog signal (luminance) with multiple modes, reducing the ability of the CFD to discriminate individual events

  6. Targeting Insulin Signaling for the Treatment of Alzheimer's Disease.

    PubMed

    Chen, Yanxing; Zhang, Jianfang; Zhang, Baorong; Gong, Cheng-Xin

    2016-01-01

    Sporadic Alzheimer's disease (AD) is caused by multiple etiological factors, among which impaired brain insulin signaling and decreased brain glucose metabolism are important metabolic factors. Contrary to previous belief that insulin would not act in the brain, studies in the last three decades have proven important roles of insulin and insulin signaling in various biological functions in the brain. Impaired brain insulin signaling or brain insulin resistance and its role in the molecular pathogenesis of sporadic AD have been demonstrated. Thus, targeting brain insulin signaling for the treatment of cognitive impairment and AD has now attracted much attention in the field of AD drug discovery. This article reviews recent studies that target brain insulin signaling, especially those investigations on intranasal insulin administration and drugs that improve insulin sensitivity, including incretins, dipeptidyl peptidase IV inhibitors, thiazolidinediones, and metformin. These drugs have been previously approved for the treatment of diabetes mellitus, which could expedite their development for the treatment of AD. Although larger clinical trials are needed for validating their efficacy for the treatment of cognitive impairment and AD, results of animal studies and clinical trials available to date are encouraging. PMID:26268336

  7. Targeting hedgehog signaling reduces self-renewal in embryonal rhabdomyosarcoma.

    PubMed

    Satheesha, S; Manzella, G; Bovay, A; Casanova, E A; Bode, P K; Belle, R; Feuchtgruber, S; Jaaks, P; Dogan, N; Koscielniak, E; Schäfer, B W

    2016-04-21

    Current treatment regimens for rhabdomyosarcoma (RMS), the most common pediatric soft tissue cancer, rely on conventional chemotherapy, and although they show clinical benefit, there is a significant risk of adverse side effects and secondary tumors later in life. Therefore, identifying and targeting sub-populations with higher tumorigenic potential and self-renewing capacity would offer improved patient management strategies. Hedgehog signaling has been linked to the development of embryonal RMS (ERMS) through mouse genetics and rare human syndromes. However, activating mutations in this pathway in sporadic RMS are rare and therefore the contribution of hedgehog signaling to oncogenesis remains unclear. Here, we show by genetic loss- and gain-of-function experiments and the use of clinically relevant small molecule modulators that hedgehog signaling is important for controlling self-renewal of a subpopulation of RMS cells in vitro and tumor initiation in vivo. In addition, hedgehog activity altered chemoresistance, motility and differentiation status. The core stem cell gene NANOG was determined to be important for ERMS self-renewal, possibly acting downstream of hedgehog signaling. Crucially, evaluating the presence of a subpopulation of tumor-propagating cells in patient biopsies identified by GLI1 and NANOG expression had prognostic significance. Hence, this work identifies novel functional aspects of hedgehog signaling in ERMS, redefines the rationale for its targeting as means to control ERMS self-renewal and underscores the importance of studying functional tumor heterogeneity in pediatric cancers. PMID:26189795

  8. Future Antidepressant Targets: Neurotrophic Factors and Related Signaling Cascades

    PubMed Central

    Schmidt, Heath D.; Banasr, Mounira; Duman, Ronald S.

    2009-01-01

    Preclinical and clinical studies demonstrate that neurotrophic factors play critical roles in the etiology and treatment of depression. While the mechanisms underlying the therapeutic efficacy of antidepressants remain unknown, increasing evidence supports a role for increased trophic support in the treatment of depression. Furthermore, antidepressants block or reverse stress-induced down regulation of neurotrophic factor expression in limbic and cortical nuclei involved in the underlying pathophysiology of depression. Thus, components of neurotrophic factor-mediated signaling cascades or the signal transduction pathways that regulate neurotrophic factor expression may provide additional targets for the development of novel, more efficacious antidepressant drugs. PMID:19802372

  9. TGF-β Signaling in Dendritic Cells Governs Colonic Homeostasis by Controlling Epithelial Differentiation and the Luminal Microbiota.

    PubMed

    Ihara, Sozaburo; Hirata, Yoshihiro; Serizawa, Takako; Suzuki, Nobumi; Sakitani, Kosuke; Kinoshita, Hiroto; Hayakawa, Yoku; Nakagawa, Hayato; Ijichi, Hideaki; Tateishi, Keisuke; Koike, Kazuhiko

    2016-06-01

    Dendritic cells (DCs) mediate host immune responses to gut microbes and play critical roles in inflammatory bowel disease. In this study, we examined the role of TGF-β signaling in DCs in colonic homeostasis. CD11c-cre Tgfbr2(fl/fl) mice developed spontaneous colitis, and CD11c-cre Tgfbr2(fl/+) mice exhibited susceptibility to dextran sulfate sodium-induced colitis. Colitis in these mice was characterized by goblet cell depletion and dysbiosis caused by Enterobacteriaceae enrichment. Wild-type mice gavaged with Enterobacteriaceae from CD11c-cre Tgfbr2(fl/fl) mice feces showed severe colitis after dextran sulfate sodium treatment, whereas those treated with Notch inhibitor exhibited attenuated colonic injury with increased goblet cell numbers, thickened mucus layer, and fewer fecal Enterobacteriaceae Wild-type mice transplanted with CD11c-cre Tgfbr2(fl/fl) bone marrow developed colitis showing increased Jagged1 and Jagged2 in DCs, increased Hes1 levels in epithelium, and goblet cell depletion. These findings suggest that TGF-β signaling in DCs regulates intestinal homeostasis by modulating epithelial cell differentiation and fecal microbiota. PMID:27183608

  10. Adaptive stress signaling in targeted therapy resistance in cancer

    PubMed Central

    Pazarentzos, Evangelos; Bivona, Trever G.

    2015-01-01

    The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. While substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumor cell survival during treatment and the development of resistance. Here, we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize or eliminate targeted therapy resistance, thereby unleashing the full potential of targeted therapies to transform many cancers from lethal to chronic or curable conditions. PMID:25703329

  11. Targeting signaling pathways with small molecules to treat autoimmune disorders.

    PubMed

    Kaminska, Bozena; Swiatek-Machado, Karolina

    2008-01-01

    Chronic activation of immune responses, mediated by inflammatory mediators and involving different effector cells of the innate and acquired immune system characterizes autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and septic shock syndrome. MAPKs are crucial intracellular mediators of inflammation. MAPK inhibitors are attractive anti-inflammatory drugs, because they are capable of reducing the synthesis of inflammation mediators at multiple levels and are effective in blocking proinflammatory cytokine signaling. Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway converts cytokine signals into genomic responses regulating proliferation and differentiation of the immune cells. JAK inhibitors are a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory and antiallergic properties. This review discusses the rationale behind current strategies of targeting MAPK and JAK/STAT signaling pathways, and the overall effects of signal transduction inhibitors in animal models of inflammatory disorders. Signal transduction inhibitors are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disorders. PMID:20477590

  12. Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

    PubMed Central

    Ahmad, Faiyaz; Murata, Taku; Simizu, Kasumi; Degerman, Eva; Maurice, Donald; Manganiello, Vincent

    2014-01-01

    By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners. PMID:25056711

  13. Targeting the EGFR signaling pathway in cancer therapy

    PubMed Central

    Seshacharyulu, Parthasarathy; Ponnusamy, Moorthy P.; Haridas, Dhanya; Jain, Maneesh; Ganti, AparK.; Batra, Surinder K.

    2012-01-01

    Introduction Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. Areas covered In this review, the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression, has been covered. Furthermore, current developments made towards targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use, has also been made. Expert opinion EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, further understanding of the system is required to develop an effective anticancer regiment. A combination therapy comprising of an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy. PMID:22239438

  14. Adiponectin signaling and function in insulin target tissues

    PubMed Central

    Ruan, Hong; Dong, Lily Q.

    2016-01-01

    Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide, posing a major threat on human health, productivity, and quality of life. Despite great progress made towards a better understanding of the molecular basis of diabetes, the available clinical counter-measures against insulin resistance, a defect that is central to obesity-linked type 2 diabetes, remain inadequate. Adiponectin, an abundant adipocyte-secreted factor with a wide-range of biological activities, improves insulin sensitivity in major insulin target tissues, modulates inflammatory responses, and plays a crucial role in the regulation of energy metabolism. However, adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention, and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation, and reveal therapeutic targets. Here, we discuss tissue- and cell-specific functions of adiponectin, with an emphasis on the regulation of adiponectin signaling pathways, and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation. Understanding better just why and how adiponectin and its downstream effector molecules work will be essential, together with empirical trials, to guide us to therapies that target the root cause(s) of type 2 diabetes and insulin resistance. PMID:26993044

  15. Conformation of the signal recognition particle in ribosomal targeting complexes

    PubMed Central

    Buskiewicz, Iwona A.; Jöckel, Johannes; Rodnina, Marina V.; Wintermeyer, Wolfgang

    2009-01-01

    The bacterial signal recognition particle (SRP) binds to ribosomes synthesizing inner membrane proteins and, by interaction with the SRP receptor, FtsY, targets them to the translocon at the membrane. Here we probe the conformation of SRP and SRP protein, Ffh, at different stages of targeting by measuring fluorescence resonance energy transfer (FRET) between fluorophores placed at various positions within SRP. Distances derived from FRET indicate that SRP binding to nontranslating ribosomes triggers a global conformational change of SRP that facilitates binding of the SRP receptor, FtsY. Binding of SRP to a signal-anchor sequence exposed on a ribosome-nascent chain complex (RNC) causes a further change of the SRP conformation, involving the flexible part of the Ffh(M) domain, which increases the affinity for FtsY of ribosome-bound SRP up to the affinity exhibited by the isolated NG domain of Ffh. This indicates that in the RNC–SRP complex the Ffh(NG) domain is fully exposed for binding FtsY to form the targeting complex. Binding of FtsY to the RNC–SRP complex results in a limited conformational change of SRP, which may initiate subsequent targeting steps. PMID:19029307

  16. Anti-metastatic treatment in colorectal cancer: targeting signaling pathways.

    PubMed

    Lemos, Clara; Sack, Ulrike; Schmid, Felicitas; Juneja, Manisha; Stein, Ulrike

    2013-01-01

    Colorectal cancer is one of the most common cancers worldwide and one of the leading causes of cancer-related death in the Western world. Tumor progression towards metastasis affects a large number of patients with colorectal cancer and seriously affects their clinical outcome. Therefore, considerable effort has been made towards the development of therapeutic strategies that can decrease or prevent colorectal cancer metastasis. Standard treatment of metastatic colorectal cancer with chemotherapy has been improved in the last 10 years by the addition of new targeted agents. The currently used antibodies bevacizumab, cetuximab and panitumumab target the VEGF and EGFR signaling pathways, which are crucial for tumor progression and metastasis. These antibodies have shown relevant efficacy in both first- and second-line treatment of metastatic colorectal cancer. Additionally, other signaling pathways, including the Wnt and HGF/Met pathways, have a well-established role in colorectal cancer progression and metastasis and constitute, therefore, promising targets for new therapeutic approaches. Several new drugs targeting these pathways, including different antibodies and small-molecule tyrosine kinase inhibitors, are currently being developed and tested in clinical trials. In this review, we summarize the new developments in this field, focusing on the inhibitors that show more promising results for use in colorectal cancer patients. PMID:22973955

  17. Giardia mitosomal protein import machinery differentially recognizes mitochondrial targeting signals.

    PubMed

    Nyindodo-Ogari, Lilian; Schwartzbach, Steven D; Estraño, Carlos E

    2014-01-01

    Giardia lamblia mitosomes are believed to be vestigial mitochondria which lack a genome. Similar to higher eukaryotes, mitosomal proteins possess either N-terminal or internal mitosomal targeting sequences. To date, some components of the higher eukaryote archetypal mitochondrial protein import apparatus have been identified and characterized in Giardia mitosomes; therefore, it is expected that mitochondrial signals will be recognized by the mitosomal protein import system. To further determine the level of conservation of the Giardia mitosome protein import apparatus, we expressed mitochondrial proteins from higher eukaryotes in Giardia. These recombinant proteins include Tom20 and Tom22; two components of the mitochondrial protein import machinery. Our results indicate that N-terminal mitochondrial targeting sequence is recognized by the mitosomal protein import machinery; however, interestingly the internal mitochondrial targeting sequences of higher eukaryotes are not recognized by the mitosome. Our results indicate that Giardia mitosome protein transport machinery shows differential recognition of higher eukaryotic mitochondria transfer signals, suggesting a divergence of the transport system in G. lamblia. Therefore, our data support the hypothesis that the protein import machinery in Giardia lamblia mitosome is an incomplete vestigial derivative of mitochondria components. PMID:25159305

  18. Ammonium stress in Arabidopsis: signaling, genetic loci, and physiological targets.

    PubMed

    Li, Baohai; Li, Guangjie; Kronzucker, Herbert J; Baluška, František; Shi, Weiming

    2014-02-01

    Ammonium (NH4(+)) toxicity is a significant ecological and agricultural issue, and an important phenomenon in cell biology. As a result of increasing soil nitrogen input and atmospheric deposition, plants have to deal with unprecedented NH4(+) stress from sources below and above ground. In this review, we describe recent advances in elucidating the signaling pathways and identifying the main physiological targets and genetic loci involved in the effects of NH4(+) stress in the roots and shoots of Arabidopsis thaliana. We outline new experimental approaches that are being used to study NH4(+) toxicity in Arabidopsis and propose an integrated view of behavior and signaling in response to NH4(+) stress in the Arabidopsis system. PMID:24126103

  19. Targeting MAPK Signaling in Age-Related Macular Degeneration

    PubMed Central

    Kyosseva, Svetlana V.

    2016-01-01

    Age-related macular degeneration (AMD) is a major cause of irreversible blindness affecting elderly people in the world. AMD is a complex multifactorial disease associated with demographic, genetics, and environmental risk factors. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in the pathogenesis of AMD. The mitogen-activated protein kinase (MAPK) signaling pathways are activated by diverse extracellular stimuli, including growth factors, mitogens, hormones, cytokines, and different cellular stressors such as oxidative stress. They regulate cell proliferation, differentiation, survival, and apoptosis. This review addresses the novel findings from human and animal studies on the relationship of MAPK signaling with AMD. The use of specific MAPK inhibitors may represent a potential therapeutic target for the treatment of this debilitating eye disease. PMID:27385915

  20. Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma

    PubMed Central

    Kudo, Masatoshi

    2012-01-01

    Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth, invasion, and metastasis, and enabled the development of molecular-targeted agents. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. In addition, the combination of sorafenib with standard treatment, such as resection, ablation, transarterial embolization, and hepatic arterial infusion chemotherapy are ongoing. This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways. Finally, the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed. PMID:23155330

  1. Signaling pathways relevant to cognition-enhancing drug targets.

    PubMed

    Ménard, Caroline; Gaudreau, Pierrette; Quirion, Rémi

    2015-01-01

    Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents. PMID:25977080

  2. Signal Recognition Particle: An essential protein targeting machine

    PubMed Central

    Akopian, David; Shen, Kuang; Zhang, Xin; Shan, Shu-ou

    2013-01-01

    The signal recognition particle (SRP) and its receptor comprise a universally conserved and essential cellular machinery that couples the synthesis of nascent proteins to their proper membrane localization. The past decade has witnessed an explosion in in-depth mechanistic investigations of this targeting machine at increasingly higher resolution. In this review, we summarize recent work that elucidates how the SRP and SRP receptor interact with the cargo protein and the target membrane, respectively, and how these interactions are coupled to a novel GTPase cycle in the SRP•SRP receptor complex to provide the driving force and enhance the fidelity of this fundamental cellular pathway. We also discuss emerging frontiers where important questions remain to be addressed. PMID:23414305

  3. Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals.

    PubMed

    Bagalkot, Vaishali; Badgeley, Marcus A; Kampfrath, Thomas; Deiuliis, Jeffrey A; Rajagopalan, Sanjay; Maiseyeu, Andrei

    2015-11-10

    Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid-latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100nm nanoparticles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and "eat-me" phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable Li

  4. Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals

    PubMed Central

    Bagalkot, Vaishali; Badgeley, Marcus A.; Kampfrath, Thomas; Deiuliis, Jeffrey A.; Rajagopalan, Sanjay; Maiseyeu, Andrei

    2016-01-01

    Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid–latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100 nm nano-particles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and “eat-me” phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable

  5. Targeting cancer by binding iron: Dissecting cellular signaling pathways

    PubMed Central

    Lui, Goldie Y.L.; Kovacevic, Zaklina; Richardson, Vera; Merlot, Angelica M.; Kalinowski, Danuta S.; Richardson, Des R.

    2015-01-01

    Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer. PMID:26125440

  6. Targeting the Mitotic Catastrophe Signaling Pathway in Cancer

    PubMed Central

    Mc Gee, Margaret M.

    2015-01-01

    Mitotic catastrophe, as defined in 2012 by the International Nomenclature Committee on Cell Death, is a bona fide intrinsic oncosuppressive mechanism that senses mitotic failure and responds by driving a cell to an irreversible antiproliferative fate of death or senescence. Thus, failed mitotic catastrophe can promote the unrestrained growth of defective cells, thereby representing a major gateway to tumour development. Furthermore, the activation of mitotic catastrophe offers significant therapeutic advantage which has been exploited in the action of conventional and targeted anticancer agents. Yet, despite its importance in tumour prevention and treatment, the molecular mechanism of mitotic catastrophe is not well understood. A better understanding of the signals that determine cell fate following failed or defective mitosis will reveal new opportunities to selectively target and enhance the programme for therapeutic benefit and reveal biomarkers to predict patient response. This review is focused on the molecular mechanism of mitotic catastrophe induction and signalling and highlights current strategies to exploit the process in cancer therapy. PMID:26491220

  7. Targeting the HGF/MET signalling pathway in cancer therapy

    PubMed Central

    Cecchi, Fabiola; Rabe, Daniel C.; Bottaro, Donald P.

    2012-01-01

    Introduction Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. Area covered The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. Expert opinion Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed phase 2 studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control. PMID:22530990

  8. Targeting the VEGF and PDGF signaling pathway in glioblastoma treatment

    PubMed Central

    Popescu, Alisa Madalina; Alexandru, Oana; Brindusa, Corina; Purcaru, Stefana Oana; Tache, Daniela Elise; Tataranu, Ligia Gabriela; Taisescu, Citto; Dricu, Anica

    2015-01-01

    Growth factor receptors dysfunction has previously been correlated with glioma cell proliferation, ability to evade apoptosis, neo-angiogenesis and resistance to therapy. Antineoplastic molecules targeting growth factor receptors are in clinical handling, however the efficacy of these compounds has often been limited by the signaling redundancy. Here, we analyzed the effect of AG1433 (a PDGFR inhibitor), SU1498 (a VEGFR inhibitor) and BEZ235 (a PI3K/Akt/mTOR signaling pathways inhibitor) on glioblastoma cells in vitro. For this study, we used a low passage glioblastoma cell line (GB9B). Assessment of cell number over 72 h showed that the growth rate was 0.3024 and the doubling time of GB9B was 2.29 days. Similar cytotoxic effects were observed by using AG1433 and SU1498 treatment, while dual PI3K/Akt/mTOR inhibition by BEZ235 was more efficient in killing glioblastoma cells than individual PDGFR or VEGFR targeting. In SU1498 treated cells, caspase 3 activity was detected 3 hours after the treatment, while activation of caspase 8 and 9 was detected 48 hours later. AG1433 treatment induced caspase 3, 8 and 9, 3 hours after the treatment. BEZ235 treatment resulted in early caspase 3 and 8 activation, 3 hours after the treatment and an activation of caspase 9, 8 hours later. PMID:26339347

  9. Targeting the Raft-Associated Akt Signaling in Hepatocellular Carcinoma

    PubMed Central

    Liu, Yuan; Lv, Ji-Yun; Shi, Jian-Fei; Yang, Mei; Liu, Shu-Hong; Li, Zhi-Wei; Wang, Hong-Bo; Zhang, Shao-Geng; Liu, Zhen-Wen; Ding, Jin-Biao; Xu, Dong-Ping; Zhao, Jing-Min

    2014-01-01

    Caveolin-1 and flotillin-1 are considered as markers of lipid rafts which can be regarded as sorting platforms for targeted transport of transmembrane proteins and are involved in fundamental cellular events such as signal transduction, cell adhesion, lipid/protein sorting, and human cancer. We addressed caveolin-1 and flotillin-1 expression in 90 human hepatocellular carcinoma (HCC) and adjacent noncancerous tissues (ANT) samples by SDS-PAGE and immunoblotting with specific antibodies. Significant caveolin-1 and flotillin-1 overexpression was found in HCC tissues compared to ANT and was confirmed by immunohistochemistry. Raft-associated Akt signaling pathway components involved in the regulation of cell survival were altered by western blotting in HCC microdomain-enriched subcellular fractions purified from paired HCC and ANT samples. Our results demonstrated that the activity of raft-associated but not total membrane Akt determines its cellular functions. Lipid rafts differ in different types of tissues, which allows for the possibility of tissue-type-specific targeting for cell survival. PMID:25243186

  10. FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells.

    PubMed

    Katoh, Yuriko; Katoh, Masaru

    2006-03-01

    WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-beta-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/beta-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEF-binding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine. PMID:16465403

  11. Honokiol inhibits melanoma stem cells by targeting notch signaling.

    PubMed

    Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu; Standing, David; Subramaniam, Dharmalingam; Umar, Shahid; Jensen, Roy A; Anant, Shrikant; Mammen, Joshua M V

    2015-12-01

    Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling. PMID:25491779

  12. Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

    PubMed Central

    McCarthy, Cathal; Kenny, Louise C.

    2016-01-01

    Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates. PMID:27604418

  13. Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia.

    PubMed

    McCarthy, Cathal; Kenny, Louise C

    2016-01-01

    Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates. PMID:27604418

  14. Molecular and Cell Signaling Targets for PTSD Pathophysiology and Pharmacotherapy

    PubMed Central

    Hauger, Richard L.; Olivares-Reyes, J. Alberto; Dautzenberg, Frank M.; Lohr, James B.; Braun, Sandra; Oakley, Robert H.

    2012-01-01

    The reasons for differences in vulnerability or resilience to the development of posttraumatic stress disorder (PTSD) are unclear. Here we review key genetic diatheses and molecular targets especially signaling pathways that mediate responses to trauma and severe stress and their potential contribution to the etiology of PTSD. Sensitization of glucocorticoid receptor (GR) signaling and dysregulation of GR modulators FKBP5, STAT5B, Bcl-2, and Bax have been implicated in PTSD pathophysiology. Furthermore, Akt, NFκB, MKP-1, and p11, which are G protein-coupled receptor (GPCR) pathway molecules, can promote or prevent sustained high anxiety and depressive-like behavior following severe stress. Agonist-induced activation of the corticotropin-releasing factor CRF1 receptor is crucial for survival in the context of serious danger or trauma, but persistent CRF1 receptor hypersignaling when a threatening or traumatic situation is no longer present is maladaptive. CRF1 receptor single nucleotide polymorphisms (SNPs) can confer susceptibility or resilience to childhood trauma while a SNP for the PAC1 receptor, another class B1 GPCR, has been linked genetically to PTSD. GRK3 phosphorylation of the CRF1 receptor protein and subsequent binding of βarrestin2 rapidly terminate Gs-coupled CRF1 receptor signaling by homologous desensitization. A deficient GRK-βarrestin2 mechanism would result in excessive CRF1 receptor signaling thereby contributing to PTSD and co-morbid posttraumatic depression. Clinical trials are needed to assess if small molecule CRF1 receptor antagonists are effective prophylactic agents when administered immediately after trauma. βarrestin2-biased agonists for CRF receptors and possibly other GPCRs implicated in PTSD, however, may prove to be novel pharmacotherapy with greater selectivity and therapeutic efficacy. PMID:22122881

  15. Targeting VEGF signalling via the neuropilin co-receptor.

    PubMed

    Djordjevic, Snezana; Driscoll, Paul C

    2013-05-01

    The blockade of tumour vascularisation and angiogenesis continues to be a focus for drug development in oncology and other pathologies. Historically, targeting vascular endothelial growth factor (VEGF) activity and its association with VEGF receptors (VEGFRs) has represented the most promising line of attack. More recently, the recognition that VEGFR co-receptors, neuropilin-1 and -2 (NRP1 and NRP2), are also engaged by specific VEGF isoforms in tandem with the VEGFRs has expanded the landscape for the development of modulators of VEGF-dependent signalling. Here, we review the recent structural characterisation of VEGF interactions with NRP subdomains and the impact this has had on drug development activity in this area. PMID:23228652

  16. Apparent speed increases at low luminance

    PubMed Central

    Vaziri-Pashkam, Maryam; Cavanagh, Patrick

    2009-01-01

    To investigate the effect of luminance on apparent speed, subjects adjusted the speed of a low-luminance rotating grating (0.31 cd/m2) to match that of a high-luminance one (1260 cd/m2). Above 4 Hz, subjects overestimated the speed of the low-luminance grating. This overestimation increased as a function of temporal rate and reached 30% around 10 Hz temporal rates. The speed overestimation became significant once the lower luminance was 2.4 log units lower than the high luminance comparison. Next the role of motion smear in speed overestimation was examined. First it was shown that the length of the perceived motion smear increased at low luminances. Second, the length of the visible smear was manipulated by changing the presentation time of the stimuli. Speed overestimation was reduced at shorter presentation times. Third the speed of a blurred stimulus was compared to a stimulus with sharp edges and the blurred stimulus was judged to move faster. These results indicate that the length of motion smear following a target contributes to its perceived speed and that this leads to speed overestimation at low luminance where motion traces lengthen because of increased persistence. PMID:19146275

  17. Flow-modulated targeted signal enhancement for volatile organic compounds.

    PubMed

    Hayward, Taylor; Gras, Ronda; Luong, Jim

    2016-06-01

    Comprehensive two-dimensional gas chromatography is a technique that is becoming more widespread within the analytical community, especially in the separation of complex mixtures. Modulation in comprehensive two-dimensional gas chromatography can be achieved by manipulating temperature or flow and offers many advantages such as increased separation power, but one underutilized advantage is increased detectability due to the reduction of peak width from the use of a modulator. A flow modulator was used to selectively target analytes for increased detectability with a standard flame ionization detector operated at 100 Hz, without the need for cryogens or advanced modulation software. By the collection of the entire peak volume followed by peak transfer rather than further separation, an increase of 12 times in peak height and detectability was realized for the analytes tested using an internal loop modulator configuration. An external loop flow modulator configuration allowed for more volatile analytes (with k < 5), and demonstrated an analyte detectability enhancement factor of at least 6. The collection loop size can be readily increased with an external loop configuration to accommodate for these naturally broader peaks. This novel flow modulated targeted signal enhancement approach was applied to industrially significant analyses like the analysis of methanol in a hydrocarbon streams. Methanol was detected at 7 ppb with a conventional flame ionization detector and without the need for pre-concentration. PMID:27120133

  18. Signal Transduction and Molecular Targets of Selected Flavonoids

    PubMed Central

    Bode, Ann M.

    2013-01-01

    Abstract Significance: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. Recent Advances: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. Critical Issues: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. Future Directions: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. Antioxid. Redox Signal. 19, 163–180. PMID:23458437

  19. sGC-cGMP signaling: target for anticancer therapy.

    PubMed

    Bian, Ka; Murad, Ferid

    2014-01-01

    The biologic endogenous production of cGMP was reported in the 1960s and followed by the demonstration of guanylyl cyclase activity and the isoforms of soluble and membrane-bound guanylyl cyclases. During the same period, cGMP specific phosphodiesterases also was discovered. Murad's lab established link between the endothelium derived relaxation factor (EDRF) and elevated cGMP concentration in the vascular system. October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide (NO) as a signaling molecule in the cardiovascular system. In contrast with the short research history of the enzymatic synthesis of NO, the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin; GTN) is the first compound of this category. Alfred Nobel (the founder of the Nobel Prize) himself had suffered from angina pectoris and was prescribed nitroglycerin for his chest pain while he refused to take due to the induction of headaches. Almost a century after its first chemical use, research in the nitric oxide and 3',5'-cyclic guanosine monophosphate (NO/cGMP) pathway has dramatically expanded and the role of NO/cGMP in physiology and pathology has been extensively studied. Soluble guanylyl cyclase (sGC) is the receptor for NO. The α1β1 heterodimer is the predominant isoform of sGC that is obligatory for catalytic activity. NO binds to the ferrous (Fe(2+)) heme at histidine 105 of the β1 subunit and leads to an increase in sGC activity and cGMP production of at least 200-fold. In this chapter, we reviewed the studies of sGC-cGMP signaling in cell proliferation; introduced our work of targeting sGC-cGMP signaling for cancer therapy; and explored the role of sGC-cGMP signaling in the chromatin-microenvironment. PMID:25015797

  20. Romidepsin targets multiple survival signaling pathways in malignant T cells

    PubMed Central

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies. PMID:26473529

  1. Romidepsin targets multiple survival signaling pathways in malignant T cells.

    PubMed

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies. PMID:26473529

  2. GABAergic Signaling as Therapeutic Target for Autism Spectrum Disorders

    PubMed Central

    Cellot, Giada; Cherubini, Enrico

    2014-01-01

    γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation–chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders. PMID:25072038

  3. T Cell Signaling Targets for Enhancing Regulatory or Effector Function

    PubMed Central

    Pan, Fan; Fan, Huimin; Liu, Zhongmin; Jiang, Shuiping

    2015-01-01

    To respond to infection, resting or naïve T cells must undergo activation, clonal expansion, and differentiation into specialized functional subsets of effector T cells. However, to prevent excessive or self-destructive immune responses, regulatory T cells (Tregs) are instrumental in suppressing the activation and function of effector cells, including effector T cells. The transcription factor Forkhead box P3 (Foxp3) regulates the expression of genes involved in the development and function of Tregs. Foxp3 interacts with other transcription factors and with epigenetic elements such as histone deacetylases (HDACs) and histone acetyltransferases. Treg suppressive function can be increased by exposure to HDAC inhibitors. The individual contributions of different HDAC family members to Treg function and their respective mechanisms of action, however, remain unclear. A study showed that HDAC6, HDAC9, and Sirtuin-1 had distinct effects on Foxp3 expression and function, suggesting that selectively targeting HDACs individually or in combination may enhance Treg stability and suppressive function. Another study showed that the receptor programmed death 1 (PD-1), a well-known inhibitor of T cell activation, halted cell cycle progression in effector T cells by inhibiting the transcription of the gene encoding the substrate-recognition component (Skp2) of the ubiquitin ligase SCFSkp2. Together, these findings reveal new signaling targets for enhancing Treg or effector T cell function that may be helpful in designing future therapies, either to increase Treg suppressive function in transplantation and autoimmune diseases or to block PD-1 function, thus increasing the magnitude of antiviral or antitumor immune responses of effector T cells. PMID:22855503

  4. Piperlongumine induces autophagy by targeting p38 signaling.

    PubMed

    Wang, Y; Wang, J-W; Xiao, X; Shan, Y; Xue, B; Jiang, G; He, Q; Chen, J; Xu, H-G; Zhao, R-X; Werle, K D; Cui, R; Liang, J; Li, Y-L; Xu, Z-X

    2013-01-01

    Piperlongumine (PL), a natural product isolated from the plant species Piper longum L., can selectively induce apoptotic cell death in cancer cells by targeting the stress response to reactive oxygen species (ROS). Here we show that PL induces cell death in the presence of benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro-methylketone (zVAD-fmk), a pan-apoptotic inhibitor, and in the presence of necrostatin-1, a necrotic inhibitor. Instead PL-induced cell death can be suppressed by 3-methyladenine, an autophagy inhibitor, and substantially attenuated in cells lacking the autophagy-related 5 (Atg5) gene. We further show that PL enhances autophagy activity without blocking autophagy flux. Application of N-acetyl-cysteine, an antioxidant, markedly reduces PL-induced autophagy and cell death, suggesting an essential role for intracellular ROS in PL-induced autophagy. Furthermore, PL stimulates the activation of p38 protein kinase through ROS-induced stress response and p38 signaling is necessary for the action of PL as SB203580, a p38 inhibitor, or dominant-negative p38 can effectively reduce PL-mediated autophagy. Thus, we have characterized a new mechanism for PL-induced cell death through the ROS-p38 pathway. Our findings support the therapeutic potential of PL by triggering autophagic cell death. PMID:24091667

  5. A molecular switch for targeting between endoplasmic reticulum (ER) and mitochondria: conversion of a mitochondria-targeting element into an ER-targeting signal in DAKAP1.

    PubMed

    Ma, Yuliang; Taylor, Susan S

    2008-04-25

    dAKAP1 (AKAP121, S-AKAP84), a dual specificity PKA scaffold protein, exists in several forms designated as a, b, c, and d. Whether dAKAP1 targets to endoplasmic reticulum (ER) or mitochondria depends on the presence of the N-terminal 33 amino acids (N1), and these N-terminal variants are generated by either alternative splicing and/or differential initiation of translation. The mitochondrial targeting motif, which is localized between residues 49 and 63, is comprised of a hydrophobic helix followed by positive charges ( Ma, Y., and Taylor, S. (2002) J. Biol. Chem. 277, 27328-27336 ). dAKAP1 is located on the cytosolic surface of mitochondria outer membrane and both smooth and rough ER membrane. A single residue, Asp(31), within the first 33 residues of dAKAP1b is required for ER targeting. Asp(31), which functions as a separate motif from the mitochondrial targeting signal, converts the mitochondrial-targeting signal into a bipartite ER-targeting signal, without destroying the mitochondria-targeting signal. Therefore dAKAP1 possesses a single targeting element capable of targeting to both mitochondria and ER, with the ER signal overlapping the mitochondria signal. The specificity of ER or mitochondria targeting is determined and switched by the availability of the negatively charged residue, Asp(31). PMID:18287098

  6. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib

    PubMed Central

    Sharman, Jeff; Di Paolo, Julie

    2016-01-01

    The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib. PMID:27247756

  7. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib.

    PubMed

    Sharman, Jeff; Di Paolo, Julie

    2016-06-01

    The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton's tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib. PMID:27247756

  8. A Generalizable Platform for Interrogating Target- and Signal-Specific Consequences of Electrophilic Modifications in Redox-Dependent Cell Signaling

    PubMed Central

    Lin, Hong-Yu; Haegele, Joseph A.; Disare, Michael T.; Lin, Qishan; Aye, Yimon

    2015-01-01

    Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized “electrophile toolbox” with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology—T-REX (targetable reactive electrophiles & oxidants)—is established by: (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein—one of several redox-sensitive regulators of the Nrf2–ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2–ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background. PMID:25909755

  9. Toxicological disruption of signaling homeostasis: Tyrosine phosphatses as targets

    EPA Science Inventory

    The protein tyrosine phosphatases (PTP) comprised a diverse group of enzymes whose activity opposes that of the tyrosine kinases. As such, the PTP have critical roles in maintaining signaling quiescence in resting cells and in restoring homeostasis by effecting signal termination...

  10. Simultaneous chromatic and luminance human electroretinogram responses

    PubMed Central

    Parry, Neil R A; Murray, Ian J; Panorgias, Athanasios; McKeefry, Declan J; Lee, Barry B; Kremers, Jan

    2012-01-01

    The parallel processing of information forms an important organisational principle of the primate visual system. Here we describe experiments which use a novel chromatic–achromatic temporal compound stimulus to simultaneously identify colour and luminance specific signals in the human electroretinogram (ERG). Luminance and chromatic components are separated in the stimulus; the luminance modulation has twice the temporal frequency of the chromatic modulation. ERGs were recorded from four trichromatic and two dichromatic subjects (1 deuteranope and 1 protanope). At isoluminance, the fundamental (first harmonic) response was elicited by the chromatic component in the stimulus. The trichromatic ERGs possessed low-pass temporal tuning characteristics, reflecting the activity of parvocellular post-receptoral mechanisms. There was very little first harmonic response in the dichromats’ ERGs. The second harmonic response was elicited by the luminance modulation in the compound stimulus and showed, in all subjects, band-pass temporal tuning characteristic of magnocellular activity. Thus it is possible to concurrently elicit ERG responses from the human retina which reflect processing in both chromatic and luminance pathways. As well as providing a clear demonstration of the parallel nature of chromatic and luminance processing in the human retina, the differences that exist between ERGs from trichromatic and dichromatic subjects point to the existence of interactions between afferent post-receptoral pathways that are in operation from the earliest stages of visual processing. PMID:22586211

  11. Therapeutic targeting of the phosphatidylinositol 3-kinase signaling pathway: novel targeted therapies and advances in the treatment of colorectal cancer

    PubMed Central

    Yu, Ming

    2012-01-01

    Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the USA, and more effective treatment of CRC is therefore needed. Advances in our understanding of the molecular pathogenesis of this malignancy have led to the development of novel molecule-targeted therapies. Among the most recent classes of targeted therapies being developed are inhibitors targeting the phosphatidylinositol 3-kinase (PI3K) signaling pathway. As one of the most frequently deregulated pathways in several human cancers, including CRC, aberrant PI3K signaling plays an important role in the growth, survival, motility and metabolism of cancer cells. Targeting this pathway therefore has considerable potential to lead to novel and more effective treatments for CRC. Preclinical and early clinical studies have revealed the potential efficacy of drugs that target PI3K signaling for the treatment of CRC. However, a major challenge that remains is to study these agents in phase III clinical trials to see whether these early successes translate into better patient outcomes. In this review we focus on providing an up-to-date assessment of our current understanding of PI3K signaling biology and its deregulation in the molecular pathogenesis of CRC. Advances in available agents and challenges in targeting the PI3K signaling pathway in CRC treatment will be discussed and placed in the context of the currently available therapies for CRC. PMID:22973417

  12. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  13. Targeting BMP signalling in cardiovascular disease and anaemia.

    PubMed

    Morrell, Nicholas W; Bloch, Donald B; ten Dijke, Peter; Goumans, Marie-Jose T H; Hata, Akiko; Smith, Jim; Yu, Paul B; Bloch, Kenneth D

    2016-02-01

    Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonic patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders including heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell-specific and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signalling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, as well as for anaemia of inflammation. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signalling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies. PMID:26461965

  14. Targeting BMP signalling in cardiovascular disease and anaemia

    PubMed Central

    Morrell, Nicholas W.; Bloch, Donald B.; ten Dijke, Peter; Goumans, Marie-Jose T.H.; Hata, Akiko; Smith, Jim; Yu, Paul B.; Bloch, Kenneth D.

    2016-01-01

    Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonal patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders of heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell- and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signaling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, and well as for anaemia of chronic disease. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signaling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies. PMID:26461965

  15. Notch signaling: an emerging therapeutic target for cancer treatment.

    PubMed

    Yuan, Xun; Wu, Hua; Xu, Hanxiao; Xiong, Huihua; Chu, Qian; Yu, Shiying; Wu, Gen Sheng; Wu, Kongming

    2015-12-01

    The Notch pathway is involved in cell proliferation, differentiation and survival. The Notch signaling pathway is one of the most commonly activated signaling pathways in cancer. Alterations include activating mutations and amplification of the Notch pathway, which play key roles in the progression of cancer. Accumulating evidence suggests that the pharmacological inhibition of this pathway can overcome chemoresistance. Efforts have been taken to develop Notch inhibitors as a single agent or in combination with clinically used chemotherapeutics to treat cancer. Some Notch inhibitors have been demonstrated to have therapeutic efficacy in preclinical studies. This review summarizes the recent studies and clinical evaluations of the Notch inhibitors in cancer. PMID:26341688

  16. Analyzing ERK 1/2 signalling and targets.

    PubMed

    Brietz, Alexandra; Schuch, Kristin Verena; Wangorsch, Gaby; Lorenz, Kristina; Dandekar, Thomas

    2016-07-19

    The ERK cascade (e.g. Raf-1) protects the heart from cell death and ischemic injury but can also turn maladaptive. Furthermore, an additional autophosphorylation of ERK2 at Thr188 (Erk1 at Thr208) allows ERK to phosphorylate nuclear targets involved in hypertrophy, stressing this additional phosphorylation as a promising pharmacological target. An in silico model was assembled and setup to reproduce different phosphorylation states of ERK 1/2 and various types of stimuli (hypertrophic versus non-hypertrophic). Synergistic and antagonistic receptor stimuli can be predicted in a semi-quantitative model, simulated time courses were experimentally validated. Furthermore, we detected new targets of ERK 1/2, which possibly contribute to the development of pathological hypertrophy. In addition we modeled further interaction partners involved in the protective and maladaptive cascade. Experimental validation included different gene expression data sets supporting key components and novel interaction partners as well as time courses in chronic heart failure. PMID:27301697

  17. Axon Targeting of Olfactory Receptor Neurons is Patterned by Coupled Hedgehog Signaling at Two Distinct Steps

    PubMed Central

    Chou, Ya-Hui; Zheng, Xiaoyan; Beachy, Philip A.; Luo, Liqun

    2010-01-01

    SUMMARY We present evidence for a novel, coupled two-step action of Hedgehog signaling in patterning axon targeting of Drosophila olfactory receptor neurons (ORNs). In the first step, differential Hedgehog pathway activity in peripheral sensory organ precursors creates ORN populations with different levels of the Patched receptor. Different Patched levels in ORNs then determine axonal responsiveness to target-derived Hedgehog in the brain: only ORN axons that do not express high levels of Patched are responsive to and require a second-step of Hedgehog signaling for target selection. Hedgehog signaling in the imaginal sensory organ precursors thus confers differential ORN responsiveness to Hedgehog-mediated axon targeting in the brain. This mechanism contributes to the spatial coordination of ORN cell bodies in the periphery and their glomerular targets in the brain. Such coupled two-step signaling may be more generally used to coordinate other spatially and temporally segregated developmental events. PMID:20850015

  18. Targeting the PDGF signaling pathway in tumor treatment

    PubMed Central

    2013-01-01

    Platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of certain cell types during embryonal development and e.g. tissue repair in the adult. Overactivity of PDGF receptor signaling, by overexpression or mutational events, may drive tumor cell growth. In addition, pericytes of the vasculature and fibroblasts and myofibroblasts of the stroma of solid tumors express PDGF receptors, and PDGF stimulation of such cells promotes tumorigenesis. Inhibition of PDGF receptor signaling has proven to useful for the treatment of patients with certain rare tumors. Whether treatment with PDGF/PDGF receptor antagonists will be beneficial for more common malignancies is the subject for ongoing studies. PMID:24359404

  19. Mitochondrial transporters as novel targets for intracellular calcium signaling.

    PubMed

    Satrústegui, Jorgina; Pardo, Beatriz; Del Arco, Araceli

    2007-01-01

    Ca(2+) signaling in mitochondria is important to tune mitochondrial function to a variety of extracellular stimuli. The main mechanism is Ca(2+) entry in mitochondria via the Ca(2+) uniporter followed by Ca(2+) activation of three dehydrogenases in the mitochondrial matrix. This results in increases in mitochondrial NADH/NAD ratios and ATP levels and increased substrate uptake by mitochondria. We review evidence gathered more than 20 years ago and recent work indicating that substrate uptake, mitochondrial NADH/NAD ratios, and ATP levels may be also activated in response to cytosolic Ca(2+) signals via a mechanism that does not require the entry of Ca(2+) in mitochondria, a mechanism depending on the activity of Ca(2+)-dependent mitochondrial carriers (CaMC). CaMCs fall into two groups, the aspartate-glutamate carriers (AGC) and the ATP-Mg/P(i) carriers, also named SCaMC (for short CaMC). The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle, and citrin, the liver AGC, is also a member of the urea cycle. Both types of CaMCs are activated by Ca(2+) in the intermembrane space and function together with the Ca(2+) uniporter in decoding the Ca(2+) signal into a mitochondrial response. PMID:17237342

  20. System for Automatic Detection and Analysis of Targets in FMICW Radar Signal

    NASA Astrophysics Data System (ADS)

    Rejfek, Luboš; Mošna, Zbyšek; Urbář, Jaroslav; Koucká Knížová, Petra

    2016-01-01

    This paper presents the automatic system for the processing of the signals from the frequency modulated interrupted continuous wave (FMICW) radar and describes methods for the primary signal processing. Further, we present methods for the detection of the targets in strong noise. These methods are tested both on the real and simulated signals. The real signals were measured using the developed at the IAP CAS experimental prototype of FMICW radar with operational frequency 35.4 GHz. The measurement campaign took place at the TU Delft, the Netherlands. The obtained results were used for development of the system for the automatic detection and analysis of the targets measured by the FMICW radar.

  1. ROS and RNS signaling in skeletal muscle: critical signals and therapeutic targets

    PubMed Central

    Michaelson, Luke P; Iler, Colleen; Ward, Christopher W

    2016-01-01

    The health of skeletal muscle is promoted by optimal nutrition and activity/exercise through the activation of molecular signaling pathways. Reactive oxygen species (ROS) or reactive nitrogen species (RNS) have been shown to modulate numerous biochemical processes including glucose uptake, gene expression, calcium signaling and contractility. In pathological conditions, ROS/RNS signaling excess or dysfunction contributes to contractile dysfunction and myopathy in skeletal muscle. Here we provide a brief review of ROS/RNS chemistry and discuss concepts of ROS/RNS signaling and its role in physiological and pathophysiological processes within striated muscle. PMID:24894146

  2. Epidermal Growth Factor Receptor-Targeted Photosensitizer Selectively Inhibits EGFR Signaling and Induces Targeted Phototoxicity In Ovarian Cancer Cells

    PubMed Central

    Abu-Yousif, Adnan O.; Moor, Anne C. E.; Zheng, Xiang; Savellano, Mark D.; Yu, Weiping; Selbo, Pål K.; Hasan, Tayyaba

    2012-01-01

    Targeted photosensitizer delivery to EGFR expressing cells was achieved in the present study using a high purity, targeted photoimmunoconjugate (PIC). When the PDT agent, benzoporphyin monoacid ring A (BPD) was coupled to an EGFR-targeting antibody (cetuximab), we observed altered cellular localization and selective phototoxicity of EGFR-positive cells, but no phototoxicity of EGFR-negative cells. Cetuximab in the PIC formulation blocked EGF-induced activation of the EGFR and downstream signaling pathways. Our results suggest that photoimmunotargeting is a useful dual strategy for the selective destruction of cancer cells and also exerts the receptor-blocking biological function of the antibody. PMID:22266098

  3. High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling

    PubMed Central

    Tummers, Bart; Van Der Burg, Sjoerd H.

    2015-01-01

    Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellular proteins to interfere with signaling of innate and adaptive immune pathways. This results in impairment of interferon and pro-inflammatory cytokine production and subsequent immune cell attraction, as well as resistance to incoming signals from the immune system. Furthermore, hrHPV avoids the killing of infected cells by interfering with antigen presentation to antigen-specific cytotoxic T lymphocytes. Thus, hrHPV has evolved multiple mechanisms to avoid detection and clearance by both the innate and adaptive immune system, the molecular mechanisms of which will be dealt with in detail in this review. PMID:26008697

  4. Role of epigenetic modifications in luminal breast cancer

    PubMed Central

    Abdel-Hafiz, Hany A; Horwitz, Kathryn B

    2015-01-01

    Luminal breast cancers represent approximately 75% of cases. Explanations into the causes of endocrine resistance are complex and are generally ascribed to genomic mechanisms. Recently, attention has been drawn to the role of epigenetic modifications in hormone resistance. We review these here. Epigenetic modifications are reversible, heritable and include changes in DNA methylation patterns, modification of histones and altered microRNA expression levels that target the receptors or their signaling pathways. Large-scale analyses indicate distinct epigenomic profiles that distinguish breast cancers from normal and benign tissues. Taking advantage of the reversibility of epigenetic modifications, drugs that target epigenetic modifiers, given in combination with chemotherapies or endocrine therapies, may represent promising approaches to restoration of therapy responsiveness in these cases. PMID:25689414

  5. Extracellular and Luminal pH Regulation by Vacuolar H+-ATPase Isoform Expression and Targeting to the Plasma Membrane and Endosomes*

    PubMed Central

    Smith, Gina A.; Howell, Gareth J.; Phillips, Clair; Muench, Stephen P.; Ponnambalam, Sreenivasan; Harrison, Michael A.

    2016-01-01

    Plasma membrane vacuolar H+-ATPase (V-ATPase) activity of tumor cells is a major factor in control of cytoplasmic and extracellular pH and metastatic potential, but the isoforms involved and the factors governing plasma membrane recruitment remain uncertain. Here, we examined expression, distribution, and activity of V-ATPase isoforms in invasive prostate adenocarcinoma (PC-3) cells. Isoforms 1 and 3 were the most highly expressed forms of membrane subunit a, with a1 and a3 the dominant plasma membrane isoforms. Correlation between plasma membrane V-ATPase activity and invasiveness was limited, but RNAi knockdown of either a isoform did slow cell proliferation and inhibit invasion in vitro. Isoform a1 was recruited to the cell surface from the early endosome-recycling complex pathway, its knockdown arresting transferrin receptor recycling. Isoform a3 was associated with the late endosomal/lysosomal compartment. Both a isoforms associated with accessory protein Ac45, knockdown of which stalled transit of a1 and transferrin-transferrin receptor, decreased proton efflux, and reduced cell growth and invasiveness; this latter effect was at least partly due to decreased delivery of the membrane-bound matrix metalloproteinase MMP-14 to the plasma membrane. These data indicate that in prostatic carcinoma cells, a1 and a3 isoform populations predominate in different compartments where they maintain different luminal pH. Ac45 plays a central role in navigating the V-ATPase to the plasma membrane, and hence it is an important factor in expression of the invasive phenotype. PMID:26912656

  6. A Review: Phytochemicals Targeting JAK/STAT Signaling and IDO Expression in Cancer.

    PubMed

    Arumuggam, Niroshaathevi; Bhowmick, Neil A; Rupasinghe, H P Vasantha

    2015-06-01

    Cancer remains a major health problem worldwide. Among many other factors, two regulatory defects that are present in most cancer cells are constitutive activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and the induction of indoleamine 2, 3-dioxygenase (IDO), an enzyme that catalyzes tryptophan degradation, through JAK/STAT signaling. Cytokine signaling activates STAT proteins in regulating cell proliferation, differentiation, and survival through modulation of target genes. Many phytochemicals can inhibit both JAK/STAT signaling and IDO expression in antigen-presenting cells by targeting different pathways. Some of the promising phytochemicals that are discussed in this review include resveratrol, cucurbitacin, curcumin, (-)-epigallocatechin gallate, and others. It is now evident that phytochemicals play key roles in inhibition of tumor proliferation and development and provide novel means for therapeutic targeting of cancer. PMID:25787773

  7. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies

    PubMed Central

    XIA, BING; QU, FULIAN; YUAN, TIAN; ZHANG, YIZHUO

    2015-01-01

    It is becoming increasingly evident that B-cell receptor (BCR) signaling is central to the development and function of B cells. BCR signaling has emerged as a pivotal pathway and a key driver of numerous B-cell lymphomas. Disruption of BCR signaling can be lethal to malignant B cells. Recently, kinase inhibitors that target BCR signaling have induced notable clinical responses. These inhibitors include spleen tyrosine kinase, mammalian target of rapamycin, phosphoinositide 3′-kinase and Bruton's tyrosine kinase (BTK). Ibrutinib, an oral irreversible BTK inhibitor, has emerged as a promising targeted therapy for patients with B-cell malignancies. The present review discusses the current understanding of BTK-mediated BCR signaling in the biology and pathobiology of normal and malignant B cells, and the cellular interaction with the tumor microenvironment. The data on ibrutinib in the preclinical and clinical settings is also discussed, and perspectives for the future use of ibrutinib are outlined. PMID:26788133

  8. Cancer Cell Signaling Pathways Targeted by Spice-Derived Nutraceuticals

    PubMed Central

    Sung, Bokyung; Prasad, Sahdeo; Yadav, Vivek R.; Aggarwal, Bharat B.

    2012-01-01

    Extensive research within the last half a century has revealed that cancer is caused by dysregulation of as many as 500 different gene products. Most natural products target multiple gene products and thus are ideally suited for prevention and treatment of various chronic diseases, including cancer. Dietary agents such as spices have been used extensively in the Eastern world for a variety of ailments for millennia, and five centuries ago they took a golden journey to the Western world. Various spice-derived nutraceuticals, including 1′-acetoxychavicol acetate, anethole, capsaicin, car-damonin, curcumin, dibenzoylmethane, diosgenin, eugenol, gambogic acid, gingerol, thymoquinone, ursolic acid, xanthohumol, and zerumbone derived from galangal, anise, red chili, black cardamom, turmeric, licorice, fenugreek, clove, kokum, ginger, black cumin, rosemary, hop, and pinecone ginger, respectively, are the focus of this review. The modulation of various transcription factors, growth factors, protein kinases, and inflammatory mediators by these spice-derived nutraceuticals are described. The anticancer potential through the modulation of various targets is also the subject of this review. Although they have always been used to improve taste and color and as a preservative, they are now also used for prevention and treatment of a wide variety of chronic inflammatory diseases, including cancer. PMID:22149093

  9. Cancer cell signaling pathways targeted by spice-derived nutraceuticals.

    PubMed

    Sung, Bokyung; Prasad, Sahdeo; Yadav, Vivek R; Aggarwal, Bharat B

    2012-01-01

    Extensive research within the last half a century has revealed that cancer is caused by dysregulation of as many as 500 different gene products. Most natural products target multiple gene products and thus are ideally suited for prevention and treatment of various chronic diseases, including cancer. Dietary agents such as spices have been used extensively in the Eastern world for a variety of ailments for millennia, and five centuries ago they took a golden journey to the Western world. Various spice-derived nutraceuticals, including 1'-acetoxychavicol acetate, anethole, capsaicin, cardamonin, curcumin, dibenzoylmethane, diosgenin, eugenol, gambogic acid, gingerol, thymoquinone, ursolic acid, xanthohumol, and zerumbone derived from galangal, anise, red chili, black cardamom, turmeric, licorice, fenugreek, clove, kokum, ginger, black cumin, rosemary, hop, and pinecone ginger, respectively, are the focus of this review. The modulation of various transcription factors, growth factors, protein kinases, and inflammatory mediators by these spice-derived nutraceuticals are described. The anticancer potential through the modulation of various targets is also the subject of this review. Although they have always been used to improve taste and color and as a preservative, they are now also used for prevention and treatment of a wide variety of chronic inflammatory diseases, including cancer. PMID:22149093

  10. Targeting TGFβ Signaling in Subchondral Bone and Articular Cartilage Homeostasis

    PubMed Central

    Zhen, Gehau; Cao, Xu

    2014-01-01

    Osteoarthritis (OA) is the most common degenerative joint disease, and there is no disease-modifying therapy for OA currently available. Targeting of articular cartilage alone may not be sufficient to halt this disease progression. Articular cartilage and subchondral bone act as a functional unit. Increasing evidence indicates that transforming growth factor β (TGFβ) plays a crucial role in maintaining homeostasis of both articular cartilage and subchondral bone. Activation of extracellular matrix latent TGFβ at the appropriate time and location is the prerequisite for its function. Aberrant activation of TGFβ in the subchondral bone in response to abnormal mechanical loading environment induces formation of osteroid islets at onset of osteoarthritis. As a result, alteration of subchondral bone structure changes the stress distribution on the articular cartilage and leads to its degeneration. Thus, inhibition of TGFβ activity in the subchondral bone may provide a new avenue of treatment for OA. In this review, we will respectively discuss the role of TGFβ in homeostasis of articular cartilage and subchondral bone as a novel target for OA therapy. PMID:24745631

  11. THE TOTAL LUMINOUS EFFICIENCY OF LUMINOUS BACTERIA.

    PubMed

    Harvey, E N

    1925-09-18

    Methods are described for measuring the light emitted by an emulsion of luminous bacteria of given thickness, and calculating the light emitted by a single bacterium, measuring 1.1 x 2.2 micra, provided there is no absorption of light in the emulsion. At the same time, the oxygen consumed by a single bacterium was measured by recording the time for the bacteria to use up .9 of the oxygen dissolved in sea water from air (20 per cent oxygen). The luminescence intensity does not diminish until the oxygen concentration falls below 2 per cent, when the luminescence diminishes rapidly. Above 2 per cent oxygen (when the oxygen dissolving in sea water from pure oxygen at 760 mm. Hg pressure = 100 per cent) the bacteria use equal amounts of oxygen in equal times, while below 2 per cent oxygen it seems very likely that rate of oxygen absorption is proportional to oxygen concentration. By measuring the time for a tube of luminous bacteria of known concentration saturated with air (20 per cent oxygen) to begin to darken (2 per cent oxygen) we can calculate the oxygen absorbed by one bacterium per second. The bacteria per cc. are counted on a blood counting slide or by a centrifugal method, after measuring the volume of a single bacterium (1.695 x 10(-12) cc.). Both methods gave results in good agreement with each other. The maximum value for the light from a single bacterium was 24 x 10(-14) lumens or 1.9 x 10(-14) candles. The maximum value for lumen-seconds per mg. of oxygen absorbed was 14. The average value for lumen-seconds per mg. O(2) was 9.25. The maximum values were selected in calculating the efficiency of light production, since some of the bacteria counted may not be producing light, although they may still be using oxygen. The "diet" of the bacteria was 60 per cent glycerol and 40 per cent peptone. To oxidize this mixture each mg. of oxygen would yield 3.38 gm. calories or 14.1 watts per second. 1 lumen per watt is therefore produced by a normal bacterium which

  12. Target sites for chemical regulation of strigolactone signaling.

    PubMed

    Nakamura, Hidemitsu; Asami, Tadao

    2014-01-01

    Demands for plant growth regulators (PGRs; chemicals that control plant growth) are increasing globally, especially in developing countries. Both positive and negative PGRs are widely used to enhance crop production and to suppress unwanted shoot growth, respectively. Strigolactones (SLs) are multifunctional molecules that function as phytohormones, inhibiting shoot branching and also functioning in the rhizospheric communication with symbiotic fungi and parasitic weeds. Therefore, it is anticipated that chemicals that regulate the functions of SLs will be widely used in agricultural applications. Although the SL biosynthetic pathway is not fully understood, it has been demonstrated that β-carotene isomerases, carotenoid cleavage dioxygenases (CCDs), and a cytochrome P450 monooxygenase are involved in strigolactone biosynthesis. A CCD inhibitor, abamine, which is also an inhibitor of abscisic acid biosynthesis, reduces the levels of SL in several plant species and reduces the germination rate of Orobanche minor seeds grown with tobacco. On the basis of the structure of abamine, several chemicals have been designed to specifically inhibit CCDs during SL synthesis. Cytochrome P450 monooxygenase is another target enzyme in the development of SL biosynthesis inhibitors, and the triazole-derived TIS series of chemicals is known to include SL biosynthesis inhibitors, although their target enzyme has not been identified. Recently, DWARF14 (D14) has been shown to be a receptor for SLs, and the D-ring moiety of SL is essential for its recognition by D14. A variety of SL agonists are currently under development and most agonists commonly contain the D-ring or a D-ring-like moiety. Several research groups have also resolved the crystal structure of D14 in the last two years. It is expected that this information on the D14 structure will be invaluable not only for developing SL agonists with novel structures but also in the design of inhibitors of SL receptors. PMID:25414720

  13. Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

    PubMed Central

    Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jianjun; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

    2016-01-01

    Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities. PMID:27446389

  14. The Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway as a Discovery Target in Stroke.

    PubMed

    Sun, Jing; Nan, Guangxian

    2016-05-01

    Protein kinases are critical modulators of a variety of intracellular and extracellular signal transduction pathways, and abnormal phosphorylation events can contribute to disease progression in a variety of diseases. As a result, protein kinases have emerged as important new drug targets for small molecule therapeutics. The mitogen-activated protein kinase (MAPK) signaling pathway transmits signals from the cell membrane to the nucleus in response to a variety of different stimuli. Because this pathway controls a broad spectrum of cellular processes, including growth, inflammation, and stress responses, it is accepted as a therapeutic target for cancer and peripheral inflammatory disorders. There is also increasing evidence that MAPK is an important regulator of ischemic and hemorrhagic cerebral vascular disease, raising the possibility that it might be a drug discovery target for stroke. In this review, we discuss the MAPK signaling pathway in association with its activation in stroke-induced brain injury. PMID:26842916

  15. Identification of Potential Drug Targets in Cancer Signaling Pathways using Stochastic Logical Models

    PubMed Central

    Zhu, Peican; Aliabadi, Hamidreza Montazeri; Uludağ, Hasan; Han, Jie

    2016-01-01

    The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no effect on the relative cell viability and the genes JAK2, Stat3, S6K, JUN, FOS, Myc, and Mcl1 are effective candidates to influence the relative cell growth. The vulnerabilities of some targets such as Myc and S6K are found to vary significantly depending on the weights of the sub-pathways; this will be indicative of the chosen target to require customization for therapy. When these targets are utilized, the response of breast cancers from different patients will be highly variable because of the known heterogeneities in signaling pathways among the patients. The targets whose vulnerabilities are invariably high might be more universally acceptable targets. PMID:26988076

  16. Endocrine disrupting chemicals targeting estrogen receptor signaling: Identification and mechanisms of action

    PubMed Central

    Shanle, Erin K.; Xu, Wei

    2011-01-01

    Many endocrine disrupting chemicals (EDCs) adversely impact estrogen signaling by interacting with two estrogen receptors (ERs): ERα and ERβ. Though the receptors have similar ligand binding and DNA binding domains, ERα and ERβ have some unique properties in terms of ligand selectivity and target gene regulation. EDCs that target ER signaling can modify genomic and non-genomic ER activity through direct interactions with ERs, indirectly through transcription factors like the aryl hydrocarbon receptor (AhR), or through modulation of metabolic enzymes that are critical for normal estrogen synthesis and metabolism. Many EDCs act through multiple mechanisms as exemplified by chemicals that bind both AhR and ER, such as 3-methylcholanthrene. Other EDCs that target ER signaling include phytoestrogens, bisphenolics, and organochlorine pesticides and many alter normal ER signaling through multiple mechanisms. EDCs can also display tissue-selective ER agonist and antagonist activities similar to selective estrogen receptor modulators (SERMs) designed for pharmaceutical use. Thus, biological effects of EDCs need to be carefully interpreted because EDCs can act through complex tissue-selective modulation of ERs and other signaling pathways in vivo. Current requirements by the U.S. Environmental Protection Agency require some in vitro and cell-based assays to identify EDCs that target ER signaling through direct and metabolic mechanisms. Additional assays may be useful screens for identifying EDCs that act through alternative mechanisms prior to further in vivo study. PMID:21053929

  17. Sensitivity Analysis of Intracellular Signaling Pathway Kinetics Predicts Targets for Stem Cell Fate Control

    PubMed Central

    Mahdavi, Alborz; Davey, Ryan E; Bhola, Patrick; Yin, Ting; Zandstra, Peter W

    2007-01-01

    Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3) pathway kinetics, a signaling network involved in embryonic stem cell (ESC) self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal. PMID:17616983

  18. Properties of unusually luminous supernovae

    NASA Astrophysics Data System (ADS)

    Pan, Tony Shih Arng

    This thesis is a theoretical study of the progenitors, event rates, and observational properties of unusually luminous supernova (SN), and aims to identify promising directions for future observations. In Chapter 2, we present model light curves and spectra of pair-instability supernovae (PISNe) over a range of progenitor masses and envelope structures for Pop III stars. We calculate the rates and detectability of PISNe, core-collapse supernovae (CCSNe), and Type Ia SNe at the Epoch of Reionization with the James Webb Space Telescope (JWST), which can be used to determine the contribution of Pop III versus Pop II stars toward ionizing the universe. Although CCSNe are the least intrinsically luminous supernovae, Chapter 5 shows that a JWST survey targeting known galaxy clusters with Einstein radii > 35" should discover gravitationally lensed CCSNe at redshifts exceeding z = 7--8. In Chapter 3, we explain the Pop II/I progenitors of observed PISNe in the local universe can be created via mergers in runaway collisions in young, dense star clusters, despite copious mass loss via line-driven winds. The PISN rate from this mechanism is consistent with the observed volumetric rate, and the Large Synoptic Survey Telescope could discover ~102 such PISNe per year. In Chapter 4, we identify 10 star clusters which may host PISN progenitors with masses up to 600 solar masses formed via runaway collisions. We estimate the probabilities of these very massive stars being in eclipsing binaries to be ≳ 30%, and find that their transits can be detected even under the contamination of the background cluster light, due to mean transit depths of ~10 6 solar luminosities. In Chapter 6, we show that there could be X-ray analogues of optically super-luminous SNe that are powered by the conversion of the kinetic energy of SN ejecta into radiation upon its collision with a dense but optically-thin circumstellar shell. We find shell configurations that can convert a large fraction of the SN

  19. Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma.

    PubMed

    Bu, Lin-Lin; Yu, Guang-Tao; Deng, Wei-Wei; Mao, Liang; Liu, Jian-Feng; Ma, Si-Rui; Fan, Teng-Fei; Hall, Bradford; Kulkarni, Ashok B; Zhang, Wen-Feng; Sun, Zhi-Jun

    2016-05-01

    Cumulative evidence suggests that constitutively activated signal transducer and activator of transcription (STAT3) may contribute to sustaining immunosuppressive status, and that inhibiting STAT3 signaling represents a potential strategy to improve antitumor immunity. In the present study, we observed that high levels phosphorylated of STAT3 are significantly associated with the markers for both myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in human head and neck squamous cell carcinoma (HNSCC). Additionally, we showed that targeting STAT3 signaling with a tolerable selective inhibitor S3I-201 significantly decreased immature myeloid cells such as MDSCs, TAMs and iDCs in genetically defined mice HNSCC model. These findings highlight that targeting STAT3 signaling may be effective to enhance antitumor immunity via myeloid suppressor cells in HNSCC. PMID:27467947

  20. Kinases and kinase signaling pathways: potential therapeutic targets in Parkinson's disease.

    PubMed

    Wang, Gang; Pan, Jing; Chen, Sheng-Di

    2012-08-01

    Complex molecular mechanisms underlying the pathogenesis of Parkinson's disease (PD) are gradually being elucidated. Accumulating genetic evidence implicates dysfunction of kinase activities and phosphorylation pathways in the pathogenesis of PD. Causative and risk gene products associated with PD include protein kinases (such as PINK1, LRRK2 and GAK) and proteins related phosphorylation signaling pathways (such as SNCA, DJ-1). PINK1, LRRK2 and several PD gene products have been associated with mitogen-activated protein (MAP) and protein kinase B (AKT) kinase signaling pathways. C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK) and p38, signaling pathways downstream of MAP, are particularly important in PD. JNK and p38 play an integral role in neuronal death. Targeting JNK or p38 signaling may offer an effective therapy for PD. Inhibitors of the ERK signaling pathway, which plays an important role in the development of l-DOPA-induced dyskinesia (LID), have been shown to attenuate this condition in animal models. In this review, we summarize experimental evidence gathered over the last decade on the role of PINK1, LRRK2 and GAK and their related phosphorylation signaling pathways (JNK, ERK, p38 and PI3K/AKT) in PD. It is speculated that improvement or modulation of these signaling pathways will reveal potential therapeutic targets for attenuation of the cardinal symptoms and motor complications in patients with PD in the future. PMID:22709943

  1. A Single Peroxisomal Targeting Signal Mediates Matrix Protein Import in Diatoms

    PubMed Central

    Gonzalez, Nicola H.; Felsner, Gregor; Schramm, Frederic D.; Klingl, Andreas; Maier, Uwe-G.; Bolte, Kathrin

    2011-01-01

    Peroxisomes are single membrane bound compartments. They are thought to be present in almost all eukaryotic cells, although the bulk of our knowledge about peroxisomes has been generated from only a handful of model organisms. Peroxisomal matrix proteins are synthesized cytosolically and posttranslationally imported into the peroxisomal matrix. The import is generally thought to be mediated by two different targeting signals. These are respectively recognized by the two import receptor proteins Pex5 and Pex7, which facilitate transport across the peroxisomal membrane. Here, we show the first in vivo localization studies of peroxisomes in a representative organism of the ecologically relevant group of diatoms using fluorescence and transmission electron microscopy. By expression of various homologous and heterologous fusion proteins we demonstrate that targeting of Phaeodactylum tricornutum peroxisomal matrix proteins is mediated only by PTS1 targeting signals, also for proteins that are in other systems imported via a PTS2 mode of action. Additional in silico analyses suggest this surprising finding may also apply to further diatoms. Our data suggest that loss of the PTS2 peroxisomal import signal is not reserved to Caenorhabditis elegans as a single exception, but has also occurred in evolutionary divergent organisms. Obviously, targeting switching from PTS2 to PTS1 across different major eukaryotic groups might have occurred for different reasons. Thus, our findings question the widespread assumption that import of peroxisomal matrix proteins is generally mediated by two different targeting signals. Our results implicate that there apparently must have been an event causing the loss of one targeting signal even in the group of diatoms. Different possibilities are discussed that indicate multiple reasons for the detected targeting switching from PTS2 to PTS1. PMID:21966495

  2. Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma.

    PubMed

    Coon, Valerie; Laukert, Tamara; Pedone, Carolyn A; Laterra, John; Kim, K Jin; Fults, Daniel W

    2010-09-01

    The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh + HGF-driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing monoclonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal antibody 5E1, (d) L2G7 + cyclopamine, or (e) L2G7 + 5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response than Shh-targeted therapy. The effect of L2G7 + 5E1 combination therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7 + cyclopamine therapy was worse. The principal mechanism by which Shh- and HGF-targeted therapies inhibited tumor growth was a potent apoptotic death response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination therapy either failed to improve or even reduced survival in mice bearing Shh + HGF-induced medulloblastomas compared with monotherapy underscores the importance of preclinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active. PMID:20807782

  3. Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

    PubMed Central

    Coon, Valerie; Laukert, Tamara; Pedone, Carolyn A.; Laterra, John; Kim, K. Jin; Fults, Daniel W.

    2010-01-01

    The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic Hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh+HGF–driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing monoclonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal antibody 5E1, (d) L2G7+cyclopamine, or (e) L2G7+5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response than Shh-targeted therapy. The effect of L2G7+5E1 combination therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7+cyclopamine therapy was worse. The principal mechanism by which Shh- and HGF-targeted therapies inhibited tumor growth was a potent apoptotic death response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination therapy either failed to improve or even reduced survival in mice bearing Shh+HGF induced medulloblastomas compared with monotherapy underscores the importance of preclinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active. PMID:20807782

  4. Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models.

    PubMed

    Salavert, Francisco; Hidago, Marta R; Amadoz, Alicia; Çubuk, Cankut; Medina, Ignacio; Crespo, Daniel; Carbonell-Caballero, Jose; Dopazo, Joaquín

    2016-07-01

    The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org. PMID:27137885

  5. Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models

    PubMed Central

    Salavert, Francisco; Hidago, Marta R.; Amadoz, Alicia; Çubuk, Cankut; Medina, Ignacio; Crespo, Daniel; Carbonell-Caballero, Jose; Dopazo, Joaquín

    2016-01-01

    The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org. PMID:27137885

  6. Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies.

    PubMed

    Oda, Katsutoshi; Ikeda, Yuji; Kashiyama, Tomoko; Miyasaka, Aki; Inaba, Kanako; Fukuda, Tomohiko; Asada, Kayo; Sone, Kenbun; Wada-Hiraike, Osamu; Kawana, Kei; Osuga, Yutaka; Fujii, Tomoyuki

    2016-07-01

    Recent developments in genomic analysis have unveiled the key signaling pathways in human cancer. However, only a limited number of molecular-targeted drugs are applicable for clinical use in gynecologic malignancies. TP53 signaling and phosphatidylinositol 3 kinase pathways are frequently mutated in cancer, and have received much attention as molecular targets in human cancers. In this review, we mainly focus on the functions of these pathways, and discuss the molecular-targeted drugs under clinical trials. The molecular-targeted drugs described in this review include dual phosphatidylinositol 3 kinase/mTOR inhibitors (NVP-BEZ235, DS-7423, SAR245409), an mTOR inhibitor (everolimus), an MEK inhibitor (pimasertib), an autophagy inhibitor (chloroquine), a cyclin-dependent kinases 4/6 inhibitor (PD0332991), and a poly (ADP-ribose) polymerase inhibitor (olaparib). PMID:27094348

  7. Application of chaos-based signal processing in the laser underwater target detection system

    SciTech Connect

    Luo, Z.; Lu, Y.; Chen, W.

    1996-12-31

    In this paper, the authors first demonstrate that the signal received from the laser underwater target detection system may be chaotic through phase space reconstruction, correlation dimension analysis and Lyapunov exponent calculation. Then the result of the correlation dimension analysis is used to construct a neural network predictor which is considered as an approximation of the basic dynamics of the received signal. Finally they introduce a chaos-based detection method and apply it to detect the underwater target. The performance of this new method is superior to that of the conventional method.

  8. The Inositide Signaling Pathway As a Target for Treating Gastric Cancer and Colorectal Cancer

    PubMed Central

    Kim, Hong Jun; Lee, Suk-young; Oh, Sang Cheul

    2016-01-01

    Gastric cancer and colorectal cancer are the leading cause of cancer mortality and have a dismal prognosis. The introduction of biological agents to treat these cancers has resulted in improved outcomes, and combination chemotherapy with targeted agents and conventional chemotherapeutic agents is regarded as standard therapy. Additional newly clarified mechanisms of oncogenesis and resistance to targeted agents require the development of new biologic agents. Aberrant activation of the inositide signaling pathway by a loss of function PTEN mutation or gain of function mutation/amplification of PIK3CA is an oncogenic mechanism in gastric cancer and colorectal cancer. Clinical trials with biologic agents that target the inositide signaling pathway are being performed to further improve treatment outcomes of patients with advanced gastric cancer and metastatic colorectal cancer (CRC). In this review we summarize the inositide signaling pathway, the targeted agents that inhibit abnormal activation of this signaling pathway and the clinical trials currently being performed in patients with advanced or metastatic gastric cancer and metastatic CRC using these targeted agents. PMID:27242542

  9. The Most Luminous Supernovae

    NASA Astrophysics Data System (ADS)

    Sukhbold, Tuguldur; Woosley, S. E.

    2016-04-01

    Recent observations have revealed a stunning diversity of extremely luminous supernovae, seemingly increasing in radiant energy without bound. We consider simple approximate limits for what existing models can provide for the peak luminosity and total radiated energy for non-relativistic, isotropic stellar explosions. The brightest possible supernova is a Type I explosion powered by a sub-millisecond magnetar with field strength B ∼ few × {10}13 G. In extreme cases, such models might reach a peak luminosity of 2× {10}46 {erg} {{{s}}}-1 and radiate a total energy of up to 4× {10}52 {erg}. Other less luminous models are also explored, including prompt hyper-energetic explosions in red supergiants, pulsational-pair instability supernovae, pair-instability supernovae, and colliding shells. Approximate analytic expressions and limits are given for each case. Excluding magnetars, the peak luminosity is near 3× {10}44 {erg} {{{s}}}-1 for the brightest models and the corresponding limit on total radiated energy is 3× {10}51 {erg}. Barring new physics, supernovae with a light output over 3× {10}51 erg must be rotationally powered, either during the explosion itself or after, the most obvious candidate being a rapidly rotating magnetar. A magnetar-based model for the recent transient event, ASASSN-15lh is presented that strains, but does not exceed the limits of what the model can provide.

  10. A novel signal-on electrochemical DNA sensor based on target catalyzed hairpin assembly strategy.

    PubMed

    Qian, Yong; Tang, Daoquan; Du, Lili; Zhang, Yanzhuo; Zhang, Lixian; Gao, Fenglei

    2015-02-15

    We describe a novel signal-on electrochemical DNA (E-DNA) sensing platform based on target-catalyzed hairpin assembly. The thiolated modified molecular beacon 1 (MB1) was first immobilized onto the Au electrode (GE) surface and then target DNA hybridized to the MB1, the opened MB1 assembled with the ferrocene (Fc)-labeled molecular beacon 2 to displace the target DNA, which became available for the next cycle of MB1-target hybridization. Moreover, Fc was confined close to the GE surface for efficient electron transfer, resulting in a current signal. Eventually, each target strand went through many cycles, resulting in numerous Fcs confining close to the GE, which leaded to the current of Fc dramatically increase. The observed signal gain was sufficient to achieve a demonstrated detection limit of 0.74 fM, with a wide linear dynamic range from 10(-15) to 10(-10)M and discriminated mismatched DNA from perfect matched target DNA with a high selectivity. Thus, the proposed E-DNA sensor would have a wide range of sensor applications because it is enzyme-free and simple to perform. PMID:25218101

  11. Silica Nanoparticles Target a Wnt Signal Transducer for Degradation and Impair Embryonic Development in Zebrafish.

    PubMed

    Yi, Hongyang; Wang, Zhuyao; Li, Xiaojiao; Yin, Min; Wang, Lihua; Aldalbahi, Ali; El-Sayed, Nahed Nasser; Wang, Hui; Chen, Nan; Fan, Chunhai; Song, Haiyun

    2016-01-01

    Many types of biocompatible nanomaterials have proven of low cytotoxicity and hold great promise for various applications in nanomedicine. Whereas they generally do not cause apparent organ toxicity or tissue damage in adult animals, it is yet to determine their biological consequences in more general contexts. In this study, we investigate how silica nanoparticles (NPs) affect cellular activities and functions under several physiological or pathological conditions. Although silica NPs are generally regarded as "inert" nanocarriers and widely employed in biomedical studies, we find that they actively affect Wnt signaling in various types of cell lines, diminishing its anti-adipogenic effect in preadipocytes and pro-invasive effect in breast cancer cells, and more significantly, impair Wnt-regulated embryonic development in Zebrafish. We further demonstrate that intracellular silica NPs block Wnt signal transduction in a way resembling signaling molecules. Specifically, silica NPs target the Dvl protein, a key component of Wnt signaling cascade, for lysosomal degradation. As Wnt signaling play significant roles in embryonic development and adipogenesis, the observed physiological effects beyond toxicity imply potential risk of obesity, or developmental defects in somitogenesis and osteogenesis upon exposure to silica NPs. In addition, given the clinical implications of Wnt signaling in tumorigenesis and cancer metastasis, our work also establishes for the first time a molecular link between nanomaterials and the Wnt signaling pathway, which opens new door for novel applications of unmodified silica NPs in targeted therapy for cancers and other critical illness. PMID:27570552

  12. Silica Nanoparticles Target a Wnt Signal Transducer for Degradation and Impair Embryonic Development in Zebrafish

    PubMed Central

    Yi, Hongyang; Wang, Zhuyao; Li, Xiaojiao; Yin, Min; Wang, Lihua; Aldalbahi, Ali; El-Sayed, Nahed Nasser; Wang, Hui; Chen, Nan; Fan, Chunhai; Song, Haiyun

    2016-01-01

    Many types of biocompatible nanomaterials have proven of low cytotoxicity and hold great promise for various applications in nanomedicine. Whereas they generally do not cause apparent organ toxicity or tissue damage in adult animals, it is yet to determine their biological consequences in more general contexts. In this study, we investigate how silica nanoparticles (NPs) affect cellular activities and functions under several physiological or pathological conditions. Although silica NPs are generally regarded as “inert” nanocarriers and widely employed in biomedical studies, we find that they actively affect Wnt signaling in various types of cell lines, diminishing its anti-adipogenic effect in preadipocytes and pro-invasive effect in breast cancer cells, and more significantly, impair Wnt-regulated embryonic development in Zebrafish. We further demonstrate that intracellular silica NPs block Wnt signal transduction in a way resembling signaling molecules. Specifically, silica NPs target the Dvl protein, a key component of Wnt signaling cascade, for lysosomal degradation. As Wnt signaling play significant roles in embryonic development and adipogenesis, the observed physiological effects beyond toxicity imply potential risk of obesity, or developmental defects in somitogenesis and osteogenesis upon exposure to silica NPs. In addition, given the clinical implications of Wnt signaling in tumorigenesis and cancer metastasis, our work also establishes for the first time a molecular link between nanomaterials and the Wnt signaling pathway, which opens new door for novel applications of unmodified silica NPs in targeted therapy for cancers and other critical illness. PMID:27570552

  13. New therapeutic strategies targeting transmembrane signal transduction in the immune system

    PubMed Central

    2010-01-01

    Single-chain receptors and multi-chain immune recognition receptors (SRs and MIRRs, respectively) represent families of structurally related but functionally different surface receptors expressed on different cells. In contrast to SRs, a distinctive and common structural characteristic of MIRR family members is that the extracellular recognition domains and intracellular signaling domains are located on separate subunits. How extracellular ligand binding triggers MIRRs and initiates intracellular signal transduction processes is not clear. A novel model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, suggests that the homooligomerization of receptor intracellular signaling domains represents a necessary and sufficient condition for receptor triggering. In this review, I demonstrate striking similarities between a consensus model of SR signaling and the SCHOOL model of MIRR signaling and show how these models, together with the lessons learned from viral pathogenesis, provide a molecular basis for novel pharmacological approaches targeting inter- and intrareceptor transmembrane interactions as universal therapeutic targets for a diverse variety of immune and other disorders. PMID:20519929

  14. Trypanosome Alternative Oxidase Possesses both an N-Terminal and Internal Mitochondrial Targeting Signal

    PubMed Central

    Hamilton, VaNae; Singha, Ujjal K.; Smith, Joseph T.; Weems, Ebony

    2014-01-01

    Recognition of mitochondrial targeting signals (MTS) by receptor translocases of outer and inner membranes of mitochondria is one of the prerequisites for import of nucleus-encoded proteins into this organelle. The MTS for a majority of trypanosomatid mitochondrial proteins have not been well defined. Here we analyzed the targeting signal for trypanosome alternative oxidase (TAO), which functions as the sole terminal oxidase in the infective form of Trypanosoma brucei. Deleting the first 10 of 24 amino acids predicted to be the classical N-terminal MTS of TAO did not affect its import into mitochondria in vitro. Furthermore, ectopically expressed TAO was targeted to mitochondria in both forms of the parasite even after deletion of first 40 amino acid residues. However, deletion of more than 20 amino acid residues from the N terminus reduced the efficiency of import. These data suggest that besides an N-terminal MTS, TAO possesses an internal mitochondrial targeting signal. In addition, both the N-terminal MTS and the mature TAO protein were able to target a cytosolic protein, dihydrofolate reductase (DHFR), to a T. brucei mitochondrion. Further analysis identified a cryptic internal MTS of TAO, located within amino acid residues 115 to 146, which was fully capable of targeting DHFR to mitochondria. The internal signal was more efficient than the N-terminal MTS for import of this heterologous protein. Together, these results show that TAO possesses a cleavable N-terminal MTS as well as an internal MTS and that these signals act together for efficient import of TAO into mitochondria. PMID:24562910

  15. Multiple target tracking and classification improvement using data fusion at node level using acoustic signals

    NASA Astrophysics Data System (ADS)

    Damarla, T. R.; Whipps, Gene

    2005-05-01

    Target tracking and classification using passive acoustic signals is difficult at best as the signals are contaminated by wind noise, multi-path effects, road conditions, and are generally not deterministic. In addition, microphone characteristics, such as sensitivity, vary with the weather conditions. The problem is further compounded if there are multiple targets, especially if some are measured with higher signal-to-noise ratios (SNRs) than the others and they share spectral information. At the U. S. Army Research Laboratory we have conducted several field experiments with a convoy of two, three, four and five vehicles traveling on different road surfaces, namely gravel, asphalt, and dirt roads. The largest convoy is comprised of two tracked vehicles and three wheeled vehicles. Two of the wheeled vehicles are heavy trucks and one is a light vehicle. We used a super-resolution direction-of-arrival estimator, specifically the minimum variance distortionless response, to compute the bearings of the targets. In order to classify the targets, we modeled the acoustic signals emanated from the targets as a set of coupled harmonics, which are related to the engine-firing rate, and subsequently used a multivariate Gaussian classifier. Independent of the classifier, we find tracking of wheeled vehicles to be intermittent as the signals from vehicles with high SNR dominate the much quieter wheeled vehicles. We used several fusion techniques to combine tracking and classification results to improve final tracking and classification estimates. We will present the improvements (or losses) made in tracking and classification of all targets. Although improvements in the estimates for tracked vehicles are not noteworthy, significant improvements are seen in the case of wheeled vehicles. We will present the fusion algorithm used.

  16. Emerging translational approaches to target STAT3 signalling and its impact on vascular disease

    PubMed Central

    Dutzmann, Jochen; Daniel, Jan-Marcus; Bauersachs, Johann; Hilfiker-Kleiner, Denise; Sedding, Daniel G.

    2015-01-01

    Acute and chronic inflammation responses characterize the vascular remodelling processes in atherosclerosis, restenosis, pulmonary arterial hypertension, and angiogenesis. The functional and phenotypic changes in diverse vascular cell types are mediated by complex signalling cascades that initiate and control genetic reprogramming. The signalling molecule's signal transducer and activator of transcription 3 (STAT3) plays a key role in the initiation and continuation of these pathophysiological changes. This review highlights the pivotal involvement of STAT3 in pathological vascular remodelling processes and discusses potential translational therapies, which target STAT3 signalling, to prevent and treat cardiovascular diseases. Moreover, current clinical trials using highly effective and selective inhibitors of STAT3 signalling for distinct diseases, such as myelofibrosis and rheumatoid arthritis, are discussed with regard to their vascular (side-) effects and their potential to pave the way for a direct use of these molecules for the prevention or treatment of vascular diseases. PMID:25784694

  17. Targeting cell death signaling in colorectal cancer: Current strategies and future perspectives

    PubMed Central

    Koehler, Bruno Christian; Jäger, Dirk; Schulze-Bergkamen, Henning

    2014-01-01

    The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use. PMID:24587670

  18. Aptamer/target binding-induced triple helix forming for signal-on electrochemical biosensing.

    PubMed

    Mao, Yinfei; Liu, Jinquan; He, Dinggen; He, Xiaoxiao; Wang, Kemin; Shi, Hui; Wen, Li

    2015-10-01

    Owing to its diversified structures, high affinity, and specificity for binding a wide range of non-nucleic acid targets, aptamer is a useful molecular recognition tool for the design of various biosensors. Herein, we report a new signal-on electrochemical biosensing platform which is based on an aptamer/target binding-induced strand displacement and triple-helix forming. The biosensing platform is composed of a signal transduction probe (STP) modified with a methylene blue (MB) and a sulfhydryl group, a triplex-forming oligonucleotides probe (TFO) and a target specific aptamer probe (Apt). Through hybridization with the TFO probe and the Apt probe, the self-assembled STP on Au electrode via Au-S bonding keeps its rigid structure. The MB on the STP is distal to the Au electrode surface. It is eT off state. Target binding releases the Apt probe and liberates the end of the MB tagged STP to fold back and form a triplex-helix structure with TFO (STP/TFO/STP), allowing MB to approach the Au electrode surface and generating measurable electrochemical signals (eT ON). As test for the feasibility and universality of this signal-on electrochemical biosensing platform, two aptamers which bind to adenosine triphosphate (ATP) and human α-thrombin (Tmb), respectively, are selected as models. The detection limit of ATP was 7.2 nM, whereas the detection limit of Tmb was 0.86 nM. PMID:26078174

  19. Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation.

    PubMed

    Inoue, T; Thomas, J H

    2000-01-01

    Caenorhabditis elegans dauer formation is controlled by multiple environmental factors. The chemosensory neuron ASI regulates dauer formation by secretion of DAF-7/TGF-beta, but the molecular targets of the DAF-7 ligand are incompletely defined and the cellular targets are unknown. We genetically characterized and cloned a putative transducer of DAF-7 signaling called daf-14 and found that it encodes a Smad protein. DAF-14 Smad has a highly unusual structure completely lacking the N-terminal domain found in all other Smad proteins known to date. daf-14 genetically interacts with daf-8, which encodes another Smad, and the interaction suggests partial functional redundancy between these two Smad proteins. We also studied the cellular targets of DAF-7 signaling by studying the sites of action of daf-14 and daf-4, the putative receptor for DAF-7. daf-14::gfp is expressed in multiple tissues that are remodeled during dauer formation. However, analysis of mosaics generated by free duplication loss and tissue-specific expression constructs indicate cell-nonautonomous function of daf-4, arguing against direct DAF-7 signaling to tissues throughout the animal. Instead, these experiments suggest the nervous system as a target of DAF-7 signaling and that the nervous system in turn regulates dauer formation by other tissues. PMID:10625546

  20. Improving VEGF-targeted therapies through inhibition of COX-2/PGE2 signaling

    PubMed Central

    Xu, Lihong; Croix, Brad St.

    2014-01-01

    Antiangiogenic agents targeting the vascular endothelial growth factor A (VEGFA) pathway play an important role in current cancer treatment modalities but are limited by alternative angiogenesis mechanisms. Recent studies suggest that enhanced signaling through a COX-2/PGE2 axis contributes to VEGF-independent tumor angiogenesis. Thus, COX-2/PGE2 inhibition may potentiate VEGF therapies.

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

    PubMed Central

    Nagaraj, Nagathihalli S

    2009-01-01

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

  2. Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin

    PubMed Central

    Grossmann, Tom N.; Yeh, Johannes T.-H.; Bowman, Brian R.; Chu, Qian; Moellering, Raymond E.; Verdine, Gregory L.

    2012-01-01

    Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of β-catenin by interfering with its constitutive degradation. β-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein–protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein–protein interactions is a biologically compelling approach toward suppression of β-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence β-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets β-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway. PMID:23071338

  3. MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling

    SciTech Connect

    Wang, Yelin; Hu, Chen; Cheng, Jun; Chen, Binquan; Ke, Qinghong; Lv, Zhen; Wu, Jian; Zhou, Yanfeng

    2014-04-18

    Highlights: • MiR-145 expression is down-regulated in HCC tissues and inversely related with IRS1 levels. • MiR-145 directly targets IRS1 in HCC cells. • Restored expression of miR-145 suppressed HCC cell proliferation and growth. • MiR-145 induced IRS1 under-expression potentially reduced downstream AKT signaling. - Abstract: Accumulating evidences have proved that dysregulation of microRNAs (miRNAs) is involved in cancer initiation and progression. In this study, we showed that miRNA-145 level was significantly decreased in hepatocellular cancer (HCC) tissues and cell lines, and its low expression was inversely associated with the abundance of insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling. We verified IRS1 as a direct target of miR-145 using Western blotting and luciferase reporter assay. Further, the restoration of miR-145 in HCC cell lines suppressed cancer cell growth, owing to down-regulated IRS1 expression and its downstream Akt/FOXO1 signaling. Our results demonstrated that miR-145 could inhibit HCC through targeting IRS1 and its downstream signaling, implicating the loss of miR-145 regulation may be a potential molecular mechanism causing aberrant oncogenic signaling in HCC.

  4. MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis.

    PubMed

    Severin, Mary E; Lee, Priscilla W; Liu, Yue; Selhorst, Amanda J; Gormley, Matthew G; Pei, Wei; Yang, Yuhong; Guerau-de-Arellano, Mireia; Racke, Michael K; Lovett-Racke, Amy E

    2016-06-01

    Transforming growth factor beta (TGFβ) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis. PMID:27190026

  5. Active targeting in a random porous medium by chemical swarm robots with secondary chemical signaling.

    PubMed

    Grančič, Peter; Štěpánek, František

    2011-08-01

    The multibody dynamics of a system of chemical swarm robots in a porous environment is investigated. The chemical swarm robots are modeled as brownian particles capable of delivering an encapsulated chemical payload toward a given target location and releasing it in response to an external stimulus. The presence of chemical signals (chemo-attractant) in the system plays a crucial role in coordinating the collective movement of the particles via chemotaxis. For a number of applications, such as distributed chemical processing and targeted drug delivery, the understanding of factors that govern the collective behavior of the particles, especially their ability to localize a given target, is of immense importance. A hybrid modeling methodology based on the combination of the brownian dynamics method and diffusion problem coupled through the chemotaxis phenomena is used to analyze the impact of a varying signaling threshold and the strength of chemotaxis on the ability of the chemical robots to fulfill their target localization mission. The results demonstrate that the selected performance criteria (the localization half time and the success rate) can be improved when an appropriate signaling process is chosen. Furthermore, for an optimum target localization strategy, the topological complexity of the porous environment needs to be reflected. PMID:21929036

  6. Active targeting in a random porous medium by chemical swarm robots with secondary chemical signaling

    NASA Astrophysics Data System (ADS)

    Grančič, Peter; Štěpánek, František

    2011-08-01

    The multibody dynamics of a system of chemical swarm robots in a porous environment is investigated. The chemical swarm robots are modeled as Brownian particles capable of delivering an encapsulated chemical payload toward a given target location and releasing it in response to an external stimulus. The presence of chemical signals (chemo-attractant) in the system plays a crucial role in coordinating the collective movement of the particles via chemotaxis. For a number of applications, such as distributed chemical processing and targeted drug delivery, the understanding of factors that govern the collective behavior of the particles, especially their ability to localize a given target, is of immense importance. A hybrid modeling methodology based on the combination of the Brownian dynamics method and diffusion problem coupled through the chemotaxis phenomena is used to analyze the impact of a varying signaling threshold and the strength of chemotaxis on the ability of the chemical robots to fulfill their target localization mission. The results demonstrate that the selected performance criteria (the localization half time and the success rate) can be improved when an appropriate signaling process is chosen. Furthermore, for an optimum target localization strategy, the topological complexity of the porous environment needs to be reflected.

  7. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family

    PubMed Central

    Shepard, H. Michael; Brdlik, Cathleen M.; Schreiber, Hans

    2008-01-01

    The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family–targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences. PMID:18982164

  8. Rationale for targeting fibroblast growth factor receptor signaling in breast cancer.

    PubMed

    André, Fabrice; Cortés, Javier

    2015-02-01

    Fibroblast growth factor receptor (FGFR) signaling is involved in multiple biological processes, including cell proliferation, survival, differentiation, migration, and apoptosis during embryonic development and adult tissue homeostasis. Given its role in the activation of critical signaling pathways, aberrant FGFR signaling has been implicated in multiple cancer types. A comprehensive search of PubMed and congress abstracts was conducted to identify reports on FGFR pathway components in breast cancer. In breast cancers, FGFR1 and FGFR4 gene amplification and single nucleotide polymorphisms in FGFR2 and FGFR4 have been detected. Commonly, these FGFR aberrations and gene amplifications lead to increased FGFR signaling and have been linked with poor prognosis and resistance to breast cancer treatments. Here, we review the role of FGFR signaling and the impact of FGFR genetic amplifications/aberrations on breast tumors. In addition, we summarize the most recent preclinical and clinical data on FGFR-targeted therapies in breast cancer. Finally, we highlight the ongoing clinical trials of the FGFR-targeted agents dovitinib, AZD4547, lucitanib, BGJ398, and JNJ-42756493, which are selected for patients with FGFR pathway-amplified breast cancer. Aberrant FGFR pathway amplification may drive some breast cancers. Inhibition of FGFR signaling is being explored in the clinic, and data from these trials may refine our ability to select patients who would best respond to these treatments. PMID:25677745

  9. Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer

    PubMed Central

    Campbell, Laura M.; Maxwell, Pamela J.; Waugh, David J.J.

    2013-01-01

    It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations. PMID:24276377

  10. The Role of Wnt Signaling in the Development of Alzheimer's Disease: A Potential Therapeutic Target?

    PubMed Central

    Xia, Shijin; Kalionis, Bill

    2014-01-01

    Accumulating evidence supports a key role for Wnt signaling in the development of the central nervous system (CNS) during embryonic development and in the regulation of the structure and function of the adult brain. Alzheimer's disease (AD) is the most common form of senile dementia, which is characterized by β-amyloid (Aβ) deposition in specific brain regions. However, the molecular mechanism underlying AD pathology remains elusive. Dysfunctional Wnt signaling is associated with several diseases such as epilepsy, cancer, metabolic disease, and AD. Increasing evidence suggests that downregulation of Wnt signaling, induced by Aβ, is associated with disease progression of AD. More importantly, persistent activation of Wnt signaling through Wnt ligands, or inhibition of negative regulators of Wnt signaling, such as Dickkopf-1 (DKK-1) and glycogen synthase kinase-3β (GSK-3β) that are hyperactive in the disease state, is able to protect against Aβ toxicity and ameliorate cognitive performance in AD. Together, these data suggest that Wnt signaling might be a potential therapeutic target of AD. Here, we review recent studies related to the progression of AD where Wnt signaling might be relevant and participate in the development of the disease. Then, we focus on the potential relevance of manipulating the Wnt signaling pathway for the treatment of AD. PMID:24883305

  11. Multiple functionally redundant signals mediate targeting to the apicoplast in the apicomplexan parasite Toxoplasma gondii.

    PubMed

    Harb, Omar S; Chatterjee, Bithi; Fraunholz, Martin J; Crawford, Michael J; Nishi, Manami; Roos, David S

    2004-06-01

    Most species of the protozoan phylum Apicomplexa harbor an endosymbiotic organelle--the apicoplast--acquired when an ancestral parasite engulfed a eukaryotic plastid-containing alga. Several hundred proteins are encoded in the parasite nucleus and are posttranslationally targeted to the apicoplast by a distinctive bipartite signal. The N-terminal 20 to 30 amino acids of nucleus-encoded apicoplast targeted proteins function as a classical signal sequence, mediating entry into the secretory pathway. Cleavage of the signal sequence exposes a transit peptide of variable length (50 to 200 amino acids) that is required for directing proteins to the apicoplast. Although these peptides are enriched in basic amino acids, their structural and functional characteristics are not well understood, which hampers the identification of apicoplast proteins that may constitute novel chemotherapeutic targets. To identify functional domains for a model apicoplast transit peptide, we generated more than 80 deletions and mutations throughout the transit peptide of Toxoplasma gondii ferredoxin NADP+ reductase (TgFNR) and examined the ability of these altered transit peptides to mediate proper targeting and processing of a fluorescent protein reporter. These studies revealed the presence of numerous functional domains. Processing can take place at multiple sites in the protein sequence and may occur outside of the apicoplast lumen. The TgFNR transit peptide contains at least two independent and functionally redundant targeting signals, each of which contains a subdomain that is required for release from or proper sorting within the endoplasmic reticulum. Certain deletion constructs traffic to multiple locations, including the apicoplast periphery, the rhoptries, and the parasitophorous vacuole, suggesting a common thread for targeting to these specialized compartments. PMID:15189987

  12. Characterization of the targeting signal in mitochondrial β-barrel proteins.

    PubMed

    Jores, Tobias; Klinger, Anna; Groß, Lucia E; Kawano, Shin; Flinner, Nadine; Duchardt-Ferner, Elke; Wöhnert, Jens; Kalbacher, Hubert; Endo, Toshiya; Schleiff, Enrico; Rapaport, Doron

    2016-01-01

    Mitochondrial β-barrel proteins are synthesized on cytosolic ribosomes and must be specifically targeted to the organelle before their integration into the mitochondrial outer membrane. The signal that assures such precise targeting and its recognition by the organelle remained obscure. In the present study we show that a specialized β-hairpin motif is this long searched for signal. We demonstrate that a synthetic β-hairpin peptide competes with the import of mitochondrial β-barrel proteins and that proteins harbouring a β-hairpin peptide fused to passenger domains are targeted to mitochondria. Furthermore, a β-hairpin motif from mitochondrial proteins targets chloroplast β-barrel proteins to mitochondria. The mitochondrial targeting depends on the hydrophobicity of the β-hairpin motif. Finally, this motif interacts with the mitochondrial import receptor Tom20. Collectively, we reveal that β-barrel proteins are targeted to mitochondria by a dedicated β-hairpin element, and this motif is recognized at the organelle surface by the outer membrane translocase. PMID:27345737

  13. Characterization of the targeting signal in mitochondrial β-barrel proteins

    PubMed Central

    Jores, Tobias; Klinger, Anna; Groß, Lucia E.; Kawano, Shin; Flinner, Nadine; Duchardt-Ferner, Elke; Wöhnert, Jens; Kalbacher, Hubert; Endo, Toshiya; Schleiff, Enrico; Rapaport, Doron

    2016-01-01

    Mitochondrial β-barrel proteins are synthesized on cytosolic ribosomes and must be specifically targeted to the organelle before their integration into the mitochondrial outer membrane. The signal that assures such precise targeting and its recognition by the organelle remained obscure. In the present study we show that a specialized β-hairpin motif is this long searched for signal. We demonstrate that a synthetic β-hairpin peptide competes with the import of mitochondrial β-barrel proteins and that proteins harbouring a β-hairpin peptide fused to passenger domains are targeted to mitochondria. Furthermore, a β-hairpin motif from mitochondrial proteins targets chloroplast β-barrel proteins to mitochondria. The mitochondrial targeting depends on the hydrophobicity of the β-hairpin motif. Finally, this motif interacts with the mitochondrial import receptor Tom20. Collectively, we reveal that β-barrel proteins are targeted to mitochondria by a dedicated β-hairpin element, and this motif is recognized at the organelle surface by the outer membrane translocase. PMID:27345737

  14. Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma.

    PubMed

    Wei, Wei; Shin, Young Shik; Xue, Min; Matsutani, Tomoo; Masui, Kenta; Yang, Huijun; Ikegami, Shiro; Gu, Yuchao; Herrmann, Ken; Johnson, Dazy; Ding, Xiangming; Hwang, Kiwook; Kim, Jungwoo; Zhou, Jian; Su, Yapeng; Li, Xinmin; Bonetti, Bruno; Chopra, Rajesh; James, C David; Cavenee, Webster K; Cloughesy, Timothy F; Mischel, Paul S; Heath, James R; Gini, Beatrice

    2016-04-11

    Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations. PMID:27070703

  15. mTORC1 signaling and IL-17 expression: Defining pathways and possible therapeutic targets.

    PubMed

    Ren, Wenkai; Yin, Jie; Duan, Jielin; Liu, Gang; Tan, Bie; Yang, Guan; Wu, Guoyao; Bazer, Fuller W; Peng, Yuanyi; Yin, Yulong

    2016-02-01

    IL-17 mediates immune responses against extracellular pathogens, and it is associated with the development and pathogenesis of various autoimmune diseases. The expression of IL-17 is regulated by various intracellular signaling cascades. Recently, it has been shown that mechanistic target of rapamycin (mTOR) signaling, comprised mainly of mTORC1 signaling, plays a critical role in IL-17 expression. Here, we review the current knowledge regarding mechanisms by which mTORC1 regulates IL-17 expression. mTORC1 positively modulates IL-17 expression through several pathways, i.e. STAT3, -HIF-1α, -S6K1, and -S6K2. Amino acids (AAs) also regulate IL-17 expression by being the energy source for Th17 cells, and by activating mTORC1 signaling. Altogether, the AA-mTORC1-IL-17 axis has broad therapeutic implications for IL-17-associated diseases, such as EAE, allergies, and colitis. PMID:26558536

  16. Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

    PubMed Central

    Yashiro, Masakazu; Matsuoka, Tasuku

    2016-01-01

    Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer. PMID:26937130

  17. [Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

    PubMed

    Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

    2015-01-01

    Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. PMID:25986976

  18. A protein targeting signal that functions in polarized epithelial cells in vivo.

    PubMed Central

    Ali, S; Hall, J; Hazlewood, G P; Hirst, B H; Gilbert, H J

    1996-01-01

    Eukaryotic membrane-associated polypeptides often contain a glycosylphosphatidylinositol (GPI) anchor that signals the attachment of GPI lipids to these proteins. The GPI anchor can function as a basolateral or apical targeting signal in mammalian cells cultured in vitro, although the function of the GPI anchor in vivo remains to be elucidated. In this study we have evaluated the effect of fusing a GPI anchor sequence to a prokaryotic reporter protein on the cellular location of the polypeptide in polarized epithelial cells of transgenic mice. The bacterial enzyme, when fused to a eukaryotic signal peptide, was secreted through the basolateral membrane of small-intestinal enterocytes; however, when the enzyme was lined to the GPI anchor sequence the polypeptide was redirected to the apical surface of the epithelial cells. These data provide the first direct evidence that the GPI anchor functions as an apical membrane protein sorting signal in polarized epithelial cells in vivo. PMID:8645168

  19. Investigation of target and ground clutter reflections on the correlation between transmitted and received noise signals

    NASA Astrophysics Data System (ADS)

    Allebach, Joshua M.; Narayanan, Ram M.; Himed, Braham

    2016-05-01

    The use of noise waveforms for radar has been popular for many years; however, not much work has been done to extend their use to long range applications. To understand the practicality of using noise for this work, the correlation values between transmitted and received signals were investigated as well as the ratio of reflected to transmitted power. This was done for both ground clutter and simple shapes representing targets of interest. Reflections from these different surfaces are dependent on the frequency of operation, polarization, angle of incidence, and target material. To act as a direct comparison to the noise waveform, a chirp signal was also reflected from these surfaces and correlated with the originally transmitted signal. For terrain, it was found that the noise offers similar correlation patterns as the chirp waveform but slightly larger reflected power for certain cases. Additionally, noise waveforms have decreased correlation values compared to chirp waveforms at low angles. For the simple shaped targets, the noise and chirp signals had similar correlation patterns, values, and power ratios.

  20. Signaling cross-talk in the resistance to HER family receptor targeted therapy

    PubMed Central

    Yamaguchi, H.; Chang, S-S; Hsu, JL.; Hung, M-C

    2013-01-01

    Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) have an important role in the initiation and progression of various types of cancer. Inhibitors targeting these receptor tyrosine kinases are some of the most successful targeted anticancer drugs widely used for cancer treatment; however, cancer cells have mechanisms of intrinsic and acquired drug resistance that pose as major obstacles in drug efficacy. Extensive studies from both clinical and laboratory research have identified several molecular mechanisms underlying resistance. Among them is the role of signaling cross-talk between the EGFR/HER2 and other signaling pathways. In this review, we focus particularly on this signaling cross-talk at the receptor, mediator and effector levels, and further discuss alternative approaches to overcome resistance. In addition to well-recognized signaling cross-talk involved in the resistance, we also introduce the cross-talk between EGFR/HER2-mediated pathways and pathways triggered by other types of receptors, including those of the Notch, Wnt and TNFR/IKK/NF-κB pathways, and discuss the potential role of targeting this cross-talk to sensitize cells to EGFR/HER2 inhibitors. PMID:23542173

  1. Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.

    PubMed

    Raynal, Noël J-M; Lee, Justin T; Wang, Youjun; Beaudry, Annie; Madireddi, Priyanka; Garriga, Judith; Malouf, Gabriel G; Dumont, Sarah; Dettman, Elisha J; Gharibyan, Vazganush; Ahmed, Saira; Chung, Woonbok; Childers, Wayne E; Abou-Gharbia, Magid; Henry, Ryan A; Andrews, Andrew J; Jelinek, Jaroslav; Cui, Ying; Baylin, Stephen B; Gill, Donald L; Issa, Jean-Pierre J

    2016-03-15

    Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer. Cancer Res; 76(6); 1494-505. ©2015 AACR. PMID:26719529

  2. Targeting cell death signalling in cancer: minimising ‘Collateral damage'

    PubMed Central

    Fox, Joanna L; MacFarlane, Marion

    2016-01-01

    Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents. PMID:27140313

  3. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways.

    PubMed

    Macdonald, James B; Macdonald, Brooke; Golitz, Loren E; LoRusso, Patricia; Sekulic, Aleksandar

    2015-02-01

    The last decade has spawned an exciting new era of oncotherapy in dermatology, including the development of targeted therapies for metastatic melanoma and basal cell carcinoma. Along with skin cancer, deregulation of the PI3K-AKT-mTOR and RAS-RAF-MEK-ERK intracellular signaling pathways contributes to tumorigenesis of a multitude of other cancers, and inhibitors of these pathways are being actively studied. Similar to other classes of targeted therapies, cutaneous adverse effects are among the most frequent toxicities observed with mitogen-activated protein kinase pathway inhibitors, PI3K-AKT-mTOR inhibitors, hedgehog signaling pathway inhibitors, and immunotherapies. Given the rapid expansion of these families of targeted treatments, dermatologists will be essential in offering dermatologic supportive care measures to cancer patients being treated with these agents. Part II of this continuing medical education article reviews skin-related adverse sequelae, including the frequency of occurrence and the implications associated with on- and off-target cutaneous toxicities of inhibitors of the RAS-RAF-MEK-ERK pathway, PI3K-AKT-mTOR pathway, hedgehog signaling pathway, and immunotherapies. PMID:25592339

  4. Block design enhances classification of 3D reach targets from electroencephalographic signals.

    PubMed

    Sosnik, Ronen; Tadipatri, Vijay Aditya; Tewfik, Ahmed H; Pellizzer, Giuseppe

    2016-08-01

    To date, decoding accuracy of actual or imagined pointing movements to targets in 3D space from electroencephalographic (EEG) signals has remained modest. The reason may pertain to the fact that these movements activate essentially the same neural networks. In this study, we aimed at testing whether repetitive pointing movements to each of the targets promotes the development of segregated neural patterns, resulting in enhanced decoding accuracy. Six human subjects generated slow or fast repetitive pointing movements with their right dominant arm to one of five targets distributed in 3D space, followed by repetitive imagery of movements to the same target or to a different target. Nine naive subjects generated both repetitive and non-repetitive slow actual movements to each of the five targets to test the effect of block design on decoding accuracy. In order to assure that base line drift and low frequency motion artifacts do not contaminate the data, the data were high-pass filtered in 4-30Hz, leaving out the delta and gamma band. For the repetitive trials, the model decoded target location with 81% accuracy, which is significantly higher than chance level. The average decoding rate of target location was only 30% for the non-repetitive trials, which is not significantly different than chance level. A subset of electrodes, mainly over the contralateral sensorimotor areas, was found to provide most of the discriminative features for all tested conditions. Time proximity between trained and tested blocks was found to enhance decoding accuracy of target location both by target non-specific and specific mechanisms. Our findings suggest that movement repetition promotes the development of distinct neural patterns, presumably by the formation of target-specific kinesthetic memory. PMID:27223628

  5. Targeting Neuropilin-1 to Inhibit VEGF Signaling in Cancer: Comparison of Therapeutic Approaches

    PubMed Central

    Gabhann, Feilim Mac; Popel, Aleksander S

    2006-01-01

    Angiogenesis (neovascularization) plays a crucial role in a variety of physiological and pathological conditions including cancer, cardiovascular disease, and wound healing. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Multiple VEGF receptors are expressed on endothelial cells, including signaling receptor tyrosine kinases (VEGFR1 and VEGFR2) and the nonsignaling co-receptor Neuropilin-1. Neuropilin-1 binds only the isoform of VEGF responsible for pathological angiogenesis (VEGF165), and is thus a potential target for inhibiting VEGF signaling. Using the first molecularly detailed computational model of VEGF and its receptors, we have shown previously that the VEGFR–Neuropilin interactions explain the observed differential effects of VEGF isoforms on VEGF signaling in vitro, and demonstrated potent VEGF inhibition by an antibody to Neuropilin-1 that does not block ligand binding but blocks subsequent receptor coupling. In the present study, we extend that computational model to simulation of in vivo VEGF transport and binding, and predict the in vivo efficacy of several Neuropilin-targeted therapies in inhibiting VEGF signaling: (a) blocking Neuropilin-1 expression; (b) blocking VEGF binding to Neuropilin-1; (c) blocking Neuropilin–VEGFR coupling. The model predicts that blockade of Neuropilin–VEGFR coupling is significantly more effective than other approaches in decreasing VEGF–VEGFR2 signaling. In addition, tumor types with different receptor expression levels respond differently to each of these treatments. In designing human therapeutics, the mechanism of attacking the target plays a significant role in the outcome: of the strategies tested here, drugs with similar properties to the Neuropilin-1 antibody are predicted to be most effective. The tumor type and the microenvironment of the target tissue are also significant in determining therapeutic efficacy of each of the treatments studied. PMID:17196035

  6. Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities.

    PubMed

    Kumar, Ankit; Kumar Singh, Umesh; Chaudhary, Anurag

    2013-05-01

    Honokiol (3,5-di-(2-propenyl)-1,1-biphenyl-2,2-diol) is a natural bioactive neolignan isolated from the genus Magnolia. In recent studies, honokiol has been observed to have anti-angiogenic, anticancer, anti-inflammatory, neuroprotective and GABA-modulating properties in vitro and in preclinical models. Honokiol and its analogs target multiple signaling pathways including NF-κB, STAT3, EGFR, mTOR and caspase-mediated common pathway, which regulate cancer initiation and progression. Honokiol and its targets of action may be helpful in the development of effective analogs and targeted cancer therapy. In this review, recent data describing the molecular targets of honokiol and its analogs with anticancer and some other bioactivities are discussed. PMID:23651094

  7. Promising Druggable Target in Head and Neck Squamous Cell Carcinoma: Wnt Signaling

    PubMed Central

    Aminuddin, Amnani; Ng, Pei Yuen

    2016-01-01

    Canonical Wnt signaling pathway, also known as Wnt/β-catenin signaling pathway, is a crucial mechanism for cellular maintenance and development. It regulates cell cycle progression, apoptosis, proliferation, migration, and differentiation. Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers. Furthermore, the canonical Wnt signaling pathway has also been described as one of the critical signaling pathways for regulation of normal stem cells as well as cancer cells with stem cell-like features, termed cancer stem cells (CSC). In this review, we will briefly describe the basic mechanisms of Wnt signaling pathway and its crucial roles in the normal regulation of cellular processes as well as in the development of cancer. Next, we will highlight the roles of canonical Wnt signaling pathway in the regulation of CSC properties namely self-renewal, differentiation, metastasis, and drug resistance abilities, particularly in head and neck squamous cell carcinoma. Finally, we will examine the findings of several recent studies which explore druggable targets in the canonical Wnt signaling pathway which could be valuable to improve the treatment outcome for head and neck cancer. PMID:27570510

  8. Promising Druggable Target in Head and Neck Squamous Cell Carcinoma: Wnt Signaling.

    PubMed

    Aminuddin, Amnani; Ng, Pei Yuen

    2016-01-01

    Canonical Wnt signaling pathway, also known as Wnt/β-catenin signaling pathway, is a crucial mechanism for cellular maintenance and development. It regulates cell cycle progression, apoptosis, proliferation, migration, and differentiation. Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers. Furthermore, the canonical Wnt signaling pathway has also been described as one of the critical signaling pathways for regulation of normal stem cells as well as cancer cells with stem cell-like features, termed cancer stem cells (CSC). In this review, we will briefly describe the basic mechanisms of Wnt signaling pathway and its crucial roles in the normal regulation of cellular processes as well as in the development of cancer. Next, we will highlight the roles of canonical Wnt signaling pathway in the regulation of CSC properties namely self-renewal, differentiation, metastasis, and drug resistance abilities, particularly in head and neck squamous cell carcinoma. Finally, we will examine the findings of several recent studies which explore druggable targets in the canonical Wnt signaling pathway which could be valuable to improve the treatment outcome for head and neck cancer. PMID:27570510

  9. The similarity between N-terminal targeting signals for protein import into different organelles and its evolutionary relevance

    PubMed Central

    Kunze, Markus; Berger, Johannes

    2015-01-01

    The proper distribution of proteins between the cytosol and various membrane-bound compartments is crucial for the functionality of eukaryotic cells. This requires the cooperation between protein transport machineries that translocate diverse proteins from the cytosol into these compartments and targeting signal(s) encoded within the primary sequence of these proteins that define their cellular destination. The mechanisms exerting protein translocation differ remarkably between the compartments, but the predominant targeting signals for mitochondria, chloroplasts and the ER share the N-terminal position, an α-helical structural element and the removal from the core protein by intraorganellar cleavage. Interestingly, similar properties have been described for the peroxisomal targeting signal type 2 mediating the import of a fraction of soluble peroxisomal proteins, whereas other peroxisomal matrix proteins encode the type 1 targeting signal residing at the extreme C-terminus. The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments. Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals. Thus, the co-existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes. PMID:26441678

  10. Single luminal epithelial progenitors can generate prostate organoids in culture

    PubMed Central

    Chua, Chee Wai; Shibata, Maho; Lei, Ming; Toivanen, Roxanne; Barlow, LaMont J.; Bergren, Sarah K.; Badani, Ketan K.; McKiernan, James M.; Benson, Mitchell C.; Hibshoosh, Hanina; Shen, Michael M.

    2014-01-01

    The intrinsic ability to display self-organizing morphogenetic properties in ex vivo culture may represent a general property of tissue stem cells. Here we show that single luminal stem/progenitor cells can generate prostate organoids in a three-dimensional culture system in the absence of stroma. Organoids generated from CARNs (castration-resistant Nkx3.1-expressing cells) or normal prostate epithelium exhibit tissue architecture containing luminal and basal cells, undergo long-term expansion in culture, and display functional androgen receptor signaling. Lineage-tracing demonstrates that luminal cells are favored for organoid formation, and generate basal cells in culture. Furthermore, tumor organoids can initiate from CARNs after oncogenic transformation, and from mouse models of prostate cancer, and can facilitate analyses of drug response. Finally, we provide evidence supporting the feasibility of organoid studies of human prostate tissue. Our studies underscore the progenitor properties of luminal cells, and identify in vitro approaches for studying prostate biology. PMID:25241035

  11. Cue Combination of Conflicting Color and Luminance Edges.

    PubMed

    Sharman, Rebecca J; McGraw, Paul V; Peirce, Jonathan W

    2015-12-01

    Abrupt changes in the color or luminance of a visual image potentially indicate object boundaries. Here, we consider how these cues to the visual "edge" location are combined when they conflict. We measured the extent to which localization of a compound edge can be predicted from a simple maximum likelihood estimation model using the reliability of chromatic (L-M) and luminance signals alone. Maximum likelihood estimation accurately predicted the pattern of results across a range of contrasts. Predictions consistently overestimated the relative influence of the luminance cue; although L-M is often considered a poor cue for localization, it was used more than expected. This need not indicate that the visual system is suboptimal but that its priors about which cue is more useful are not flat. This may be because, although strong changes in chromaticity typically represent object boundaries, changes in luminance can be caused by either a boundary or a shadow. PMID:27551364

  12. High-luminance LEDs replace incandescent lamps in new applications

    NASA Astrophysics Data System (ADS)

    Evans, David L.

    1997-04-01

    The advent of high luminance AlInGaP and InGaN LED technologies has prompted the use of LED devices in new applications formally illuminated by incandescent lamps. The luminous efficiencies of these new LED technologies equals or exceeds that attainable with incandescent sources, with reliability factors that far exceed those of incandescent sources. The need for a highly efficient, dependable, and cost effective replacement for incandescent lamps is being fulfilled with high luminance LED lamps. This paper briefly described some of the new applications incorporating high luminance LED lamps, traffic signals and roadway signs for traffic management, automotive exterior lighting, active matrix and full color displays for commercial advertising, and commercial aircraft panel lighting and military aircraft NVG compatible lighting.

  13. Cue Combination of Conflicting Color and Luminance Edges

    PubMed Central

    Sharman, Rebecca J; McGraw, Paul V

    2015-01-01

    Abrupt changes in the color or luminance of a visual image potentially indicate object boundaries. Here, we consider how these cues to the visual “edge” location are combined when they conflict. We measured the extent to which localization of a compound edge can be predicted from a simple maximum likelihood estimation model using the reliability of chromatic (L−M) and luminance signals alone. Maximum likelihood estimation accurately predicted the pattern of results across a range of contrasts. Predictions consistently overestimated the relative influence of the luminance cue; although L−M is often considered a poor cue for localization, it was used more than expected. This need not indicate that the visual system is suboptimal but that its priors about which cue is more useful are not flat. This may be because, although strong changes in chromaticity typically represent object boundaries, changes in luminance can be caused by either a boundary or a shadow. PMID:27551364

  14. Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling.

    PubMed

    Link, Andrea S; Kurinna, Svitlana; Havlicek, Steven; Lehnert, Sandra; Reichel, Martin; Kornhuber, Johannes; Winner, Beate; Huth, Tobias; Zheng, Fang; Werner, Sabine; Alzheimer, Christian

    2016-08-01

    The transforming growth factor-β (TGF-β) family member activin A exerts multiple neurotrophic and protective effects in the brain. Activin also modulates cognitive functions and affective behavior and is a presumed target of antidepressant therapy. Despite its important role in the injured and intact brain, the mechanisms underlying activin effects in the CNS are still largely unknown. Our goal was to identify the first target genes of activin signaling in the hippocampus in vivo. Electroconvulsive seizures, a rodent model of electroconvulsive therapy in humans, were applied to C57BL/6J mice to elicit a strong increase in activin A signaling. Chromatin immunoprecipitation experiments with hippocampal lysates subsequently revealed that binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-β signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. Underlining the significance of these findings, activin treatment also induced PMEPA1 and KDM6B expression in human forebrain neurons generated from embryonic stem cells suggesting interspecies conservation of activin effects in mammalian neurons. Importantly, physiological stimuli such as provided by environmental enrichment proved already sufficient to engender a rapid and significant induction of activin signaling concomitant with an upregulation of Pmepa1 and Kdm6b expression. Taken together, our study identified the first target genes of activin signaling in the brain. With the induction of Kdm6b expression, activin is likely to gain impact on a presumed epigenetic regulator of activity-dependent neuronal plasticity. PMID:26215835

  15. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.

    PubMed

    Justilien, Verline; Fields, Alan P

    2015-02-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy. PMID:25646180

  16. '2A-Like' Signal Sequences Mediating Translational Recoding: A Novel Form of Dual Protein Targeting.

    PubMed

    Roulston, Claire; Luke, Garry A; de Felipe, Pablo; Ruan, Lin; Cope, Jonathan; Nicholson, John; Sukhodub, Andriy; Tilsner, Jens; Ryan, Martin D

    2016-08-01

    We report the initial characterization of an N-terminal oligopeptide '2A-like' sequence that is able to function both as a signal sequence and as a translational recoding element. Owing to this translational recoding activity, two forms of nascent polypeptide are synthesized: (i) when 2A-mediated translational recoding has not occurred: the nascent polypeptide is fused to the 2A-like N-terminal signal sequence and the fusion translation product is targeted to the exocytic pathway, and, (ii) a translation product where 2A-mediated translational recoding has occurred: the 2A-like signal sequence is synthesized as a separate translation product and, therefore, the nascent (downstream) polypeptide lacks the 2A-like signal sequence and is localized to the cytoplasm. This type of dual-functional signal sequence results, therefore, in the partitioning of the translation products between the two sub-cellular sites and represents a newly described form of dual protein targeting. PMID:27161495

  17. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling.

    PubMed

    Moreno, Estefanía; Andradas, Clara; Medrano, Mireia; Caffarel, María M; Pérez-Gómez, Eduardo; Blasco-Benito, Sandra; Gómez-Cañas, María; Pazos, M Ruth; Irving, Andrew J; Lluís, Carme; Canela, Enric I; Fernández-Ruiz, Javier; Guzmán, Manuel; McCormick, Peter J; Sánchez, Cristina

    2014-08-01

    The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology. PMID:24942731

  18. Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling*

    PubMed Central

    Moreno, Estefanía; Andradas, Clara; Medrano, Mireia; Caffarel, María M.; Pérez-Gómez, Eduardo; Blasco-Benito, Sandra; Gómez-Cañas, María; Pazos, M. Ruth; Irving, Andrew J.; Lluís, Carme; Canela, Enric I.; Fernández-Ruiz, Javier; Guzmán, Manuel; McCormick, Peter J.; Sánchez, Cristina

    2014-01-01

    The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology. PMID:24942731

  19. From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling

    PubMed Central

    Ntziachristos, Panagiotis; Lim, Jing Shan; Sage, Julien; Aifantis, Iannis

    2014-01-01

    Since Notch phenotypes in Drosophila melanogaster were identified 100 years, Notch signaling has been extensively characterized as a regulator of cell fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this Perspective, we discuss the pro-tumorigenic and tumor suppressive functions of Notch signaling and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. PMID:24651013

  20. Core-glycosylated mucin-like repeats from MUC1 are an apical targeting signal.

    PubMed

    Kinlough, Carol L; Poland, Paul A; Gendler, Sandra J; Mattila, Polly E; Mo, Di; Weisz, Ora A; Hughey, Rebecca P

    2011-11-11

    MUC1 is efficiently delivered to the apical surface of polarized Madin-Darby canine kidney (MDCK) cells by transit through apical recycling endosomes, a route associated with delivery of apical proteins with glycan-dependent targeting signals. However, a role for glycans in MUC1 sorting has not been established. A key feature of MUC1 is a heavily O-glycosylated mucin-like domain with a variable number of nearly perfect tandem repeats and adjacent imperfect repeats. Metabolic labeling, cell surface biotinylation, immobilized lectins, and confocal immunofluorescence microscopy were used to characterize the polarized delivery of MUC1 mutants and chimeras in MDCK cells to identify the apical targeting signal. Both the interleukin-2 receptor α subunit (Tac) and a chimera where the Tac ectodomain replaced that of MUC1 were delivered primarily to the basolateral surface. Attachment of the MUC1 mucin-like domain to the N terminus of Tac enhanced apical but not basolateral delivery when compared with Tac. Conversely, deletions within the mucin-like domain in MUC1 reduced apical but not basolateral delivery when compared with MUC1. In pull-down assays with lectins, we found a notable difference in the presence of core 1 O-glycans, but not poly-N-acetyllactosamine, in apically targeted MUC1 and chimeras when compared with Tac. Consistent with these data, we found no effect on MUC1 targeting when galectin-3, with preference for poly-N-acetyllactosamine, was depleted from polarized MDCK cells. However, we did block the apical targeting activity of the mucin-like repeats when we overexpressed CMP-Neu5Ac:GalNAc-Rα2,6-sialyltransferase-1 to block core O-glycan synthesis. The cumulative data indicate that the core-glycosylated mucin-like repeats of MUC1 constitute an apical targeting signal. PMID:21937430

  1. Compensatory pathways in oncogenic kinase signaling and resistance to targeted therapies: six degrees of separation.

    PubMed

    Trusolino, Livio; Bertotti, Andrea

    2012-10-01

    The efficacy of targeted therapies against mutationally activated kinases is typically limited by the engagement of growth-promoting cues that compensate for inhibition of the targeted kinase. Initial studies have highlighted the contribution of genomic alterations, functional characteristics, and signaling feedback loops--all intrinsic to cancer cells--in sustaining such substitute activities. New evidence now indicates that the relative expression of growth factor ligands produced by the tumor microenvironment can relay redundant survival pathways, which may broadly impair responsiveness to kinase inhibitors. PMID:23071031

  2. Sorting and targeting of melanosomal membrane proteins: signals, pathways, and mechanisms.

    PubMed

    Setaluri, V

    2000-06-01

    Newly synthesized melanosomal proteins, like many other cellular proteins, traverse through a series of intracellular compartments en route to melanosomes. Entry and exit of proteins through these compartments is orchestrated by cellular sorting machinery that recognize specific sorting signals. Melanosomal membrane proteins begin their intracellular journey upon co-translational importation into the endoplasmic reticulum (ER). The biosynthetic output of tyrosinase, the key melanogenic enzyme, appears to be regulated by quality-control events at the ER, the 'port of entry' to the secretory pathway. Following maturation in the ER and through the Golgi, the sorting of these proteins in the trans-Golgi network for intracellular retention and transport along endosome/lysosome pathway requires cytoplasmically exposed signals. A di-leucine motif, present in the cytoplasmic tails of most melanosomal proteins, and its interaction with adaptor protein (AP) complexes, specifically AP-3, are critical for these events. Defects in sorting signals and the cytosolic components that interact with these signals result in a number of murine coat color phenotypes and cause human pigmentary disorders. Thus, missense or frame-shift mutations that produce truncated tyrosinase lacking the melanosomal sorting signal(s) appear to be responsible for murine platinum coat color phenotypes and a proportion of human oculocutaneous albinism-1; mutations in AP-3 appear to be responsible for the mocha phenotype in mice and Hermansky-Pudlak-like syndrome in man. Additional signals and sorting steps downstream of AP-3 appear to be required for endosomal sorting and targeting proteins to melanosomes. Signals and mechanisms that sequester melanosomal proteins from endosomes/lysosomes are not understood. Potential candidates that mediate such processes include proteins encoded by lyst and pallid genes. The common occurrence of abnormalities in melanosomes in many storage-pool disorders suggests that

  3. Differential Targeting of Gβγ-Subunit Signaling with Small Molecules

    NASA Astrophysics Data System (ADS)

    Bonacci, Tabetha M.; Mathews, Jennifer L.; Yuan, Chujun; Lehmann, David M.; Malik, Sundeep; Wu, Dianqing; Font, Jose L.; Bidlack, Jean M.; Smrcka, Alan V.

    2006-04-01

    G protein βγ subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gβγ subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gβγ subunit functions. Several compounds bound to Gβγ subunits with affinities from 0.1 to 60 μM and selectively modulated functional Gβγ-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.

  4. Characterization of FGFR signaling pathway as therapeutic targets for sarcoma patients

    PubMed Central

    Zhou, Wen-Ya; Zheng, Hong; Du, Xiao-Ling; Yang, Ji-Long

    2016-01-01

    The fibroblast growth factor receptor (FGFR) family plays important roles in regulating cell growth, proliferation, survival, differentiation and angiogenesis. Deregulation of the FGF/FGFR signaling pathway has been associated with multiple development syndromes and cancers, and thus therapeutic strategies targeting FGFs and FGFR in human cancer are currently being explored. However, few studies on the FGF/FGFR pathway have been conducted in sarcoma, which has a poor outcome with traditional treatments such as surgery, chemotherapy, and radiotherapy. Hence, in the present review, we provide an overview of the role of the FGF/FGFR pathway signal in sarcoma and FGFR inhibitors, which might be new targets for the treatment of sarcomas according to recent research. PMID:27458533

  5. Abnormal proteins can form aggresome in yeast: aggresome-targeting signals and components of the machinery

    PubMed Central

    Wang, Yan; Meriin, Anatoli B.; Zaarur, Nava; Romanova, Nina V.; Chernoff, Yury O.; Costello, Catherine E.; Sherman, Michael Y.

    2009-01-01

    In mammalian cells, abnormal proteins that escape proteasome-dependent degradation form small aggregates that can be transported into a centrosome-associated structure, called an aggresome. Here we demonstrate that in yeast a single aggregate formed by the huntingtin exon 1 with an expanded polyglutamine domain (103QP) represents a bona fide aggresome that colocalizes with the spindle pole body (the yeast centrosome) in a microtubule-dependent fashion. Since a polypeptide lacking the proline-rich region (P-region) of huntingtin (103Q) cannot form aggresomes, this domain serves as an aggresome-targeting signal. Coexpression of 103Q with 25QP, a soluble polypeptide that also carries the P-region, led to the recruitment of 103Q to the aggresome via formation of hetero-oligomers, indicating the aggresome targeting in trans. To identify additional factors involved in aggresome formation and targeting, we purified 103QP aggresomes and 103Q aggregates and identified the associated proteins using mass spectrometry. Among the aggresome-associated proteins we identified, Cdc48 (VCP/p97) and its cofactors, Ufd1 and Nlp4, were shown genetically to be essential for aggresome formation. The 14-3-3 protein, Bmh1, was also found to be critical for aggresome targeting. Its interaction with the huntingtin fragment and its role in aggresome formation required the huntingtin N-terminal N17 domain, adjacent to the polyQ domain. Accordingly, the huntingtin N17 domain, along with the P-region, plays a role in aggresome targeting. We also present direct genetic evidence for the protective role of aggresomes by demonstrating genetically that aggresome targeting of polyglutamine polypeptides relieves their toxicity.—Wang, Y., Meriin, A. B., Zaarur, N., Romanova, N. V., Chernoff, Y. O., Costello, C. E., Sherman, M. Y. Abnormal proteins can form aggresome in yeast: aggresome-targeting signals and components of the machinery. PMID:18854435

  6. Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway.

    PubMed

    Fu, Ying-Zi; Yan, Yuan-Yuan; He, Miao; Xiao, Qing-Huan; Yao, Wei-Fan; Zhao, Lin; Wu, Hui-Zhe; Yu, Zhao-Jin; Zhou, Ming-Yi; Lv, Mu-Tian; Zhang, Shan-Shan; Chen, Jian-Jun; Wei, Min-Jie

    2016-02-01

    Breast cancer stem cells (BCSCs) are believed to be responsible for tumor chemoresistance, recurrence, and metastasis formation. Salinomycin (SAL), a carboxylic polyether ionophore, has been reported to act as a selective breast CSC inhibitor. However, the molecular mechanisms underlying SAL-induced cytotoxicity on BCSCs remain unclear. The Hedgehog (Hh) signaling pathway plays an important role in CSC maintenance and carcinogenesis. Here, we investigated whether SAL induces cytotoxicity on BCSCs through targeting Hh pathway. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain breast CSC-enriched MCF-7 mammospheres (MCF-7 MS). MCF-7 MS cells possessed typical BCSC properties, such as CD44+CD24-/low phenotype, high expression of OCT4 (a stem cell marker), increased colony-forming ability, strong migration and invasion capabilities, differentiation potential, and strong tumorigenicity in xenografted mice. SAL exhibited selective cytotoxicity to MCF-7 MS cells relative to MCF-7 cells. The Hh pathway was highly activated in BCSC-enriched MCF-7 MS cells and SAL inhibited Hh signaling activation by downregulating the expression of critical components of the Hh pathway such as PTCH, SMO, Gli1, and Gli2, and subsequently repressing the expression of their essential downstream targets including C-myc, Bcl-2, and Snail (but not cyclin D1). Conversely, Shh-induced Hh signaling activation could largely reverse SAL-mediated inhibitory effects. These findings suggest that SAL-induced selective cytotoxicity against MCF-7 MS cells is associated with the inhibition of Hh signaling activation and the expression of downstream targets and the Hh pathway is an important player and a possible drug target in the pathogenesis of BCSCs. PMID:26718029

  7. The Rac1 hypervariable region in targeting and signaling: a tail of many stories.

    PubMed

    Lam, B Daniel; Hordijk, Peter L

    2013-01-01

    Cellular signaling by small GTPases is critically dependent on proper spatio-temporal orchestration of activation and output. In addition to their core G (guanine nucleotide binding)-domain, small GTPases comprise a hypervariable region (HVR) and a lipid anchor that are generally accepted to control subcellullar localization. The HVR encodes in many small GTPases a polybasic region (PBR) that permits charge-mediated association to the inner leaflet of the plasma membrane or to intracellular organelles. Over the past 15-20 years, evidence has accumulated for specific protein-protein interactions, mediated by the HVR, that control both targeting and signaling specificity of small GTPases. Using the RhoGTPase Rac1 as a paradigm we here review a series of protein partners that require the Rac1 HVR for association and that control various aspects of localized Rac1 signaling. Some of these proteins represent Rac1 activators, whereas others mediate Rac1 inactivation and degradation and yet others potentiate Rac1 downstream signaling. Finally, evidence is discussed which shows that the HVR of Rac1 also contributes to effector interactions, co-operating with the N-terminal effector domain. The complexity of localized Rac1 signaling, reviewed here, is most likely exemplary for many other small GTPases as well, representing a challenge to identify and define similar mechanisms controlling the specific signaling induced by small GTPases. PMID:23354415

  8. Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations

    PubMed Central

    Moschetta, M; Reale, A; Marasco, C; Vacca, A; Carratù, M R

    2014-01-01

    The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signalling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient- and energy-dependent signals. It activates PKC-α and Akt and regulates the actin cytoskeleton. Deregulation of the mTOR-signalling pathway (PI3K amplification/mutation, PTEN loss of function, Akt overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signalling pathway. PMID:24780124

  9. Dendritic cell specific targeting of MyD88 signalling pathways in vivo.

    PubMed

    Arnold-Schrauf, Catharina; Berod, Luciana; Sparwasser, Tim

    2015-01-01

    Dendritic cells (DCs) are key regulators of both innate and adaptive immunity. During infection, DCs recognise pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) including the Toll-like receptor (TLR) family. TLRs mainly signal via the adaptor protein MyD88. This signalling pathway is required for immune protection during many infections, which are lethal in the absence of MyD88. However, the cell type specific importance of this pathway during both innate and adaptive immune responses against pathogens in vivo remains ill-defined. We discuss recent findings from conditional KO or gain-of-function mouse models targeting TLR/MyD88 signalling pathways in DCs and other myeloid cells during infection. While the general assumption that MyD88-dependent recognition by DCs is essential for inducing protective immunity holds true in some instances, the results surprisingly indicate a much more complex context-dependent requirement for this pathway in DCs and other myeloid or lymphoid cell-types in vivo. Furthermore, we highlight the advantages of Cre-mediated DC targeting approaches and their possible limitations. We also present future perspectives on the development of new genetic mouse models to target distinct DC subsets in vivo. Such models will serve to understand the functional heterogeneity of DCs in vivo. PMID:25403892

  10. PITPs as Targets for Selectively Interfering With Phosphoinositide Signaling in Cells

    PubMed Central

    Nile, Aaron H.; Tripathi, Ashutosh; Yuan, Peihua; Mousley, Carl J.; Suresh, Sundari; Wallace, Iain Michael; Shah, Sweety D.; Pohlhaus, Denise Teotico; Temple, Brenda; Nislow, Corey; Giaever, Guri; Tropsha, Alexander; Davis, Ronald W.; St Onge, Robert P.; Bankaitis, Vytas A.

    2013-01-01

    Sec14-like phosphatidylinositol transfer proteins (PITPs) integrate diverse territories of intracellular lipid metabolism with stimulated phosphatidylinositol-4-phosphate production, and are discriminating portals for interrogating phosphoinositide signaling. Yet, neither Sec14-like PITPs, nor PITPs in general, have been exploited as targets for chemical inhibition for such purposes. Herein, we validate the first small molecule inhibitors (SMIs) of the yeast PITP Sec14. These SMIs are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and are effective inhibitors in vitro and in vivo. We further establish Sec14 is the sole essential NPPM target in yeast, that NPPMs exhibit exquisite targeting specificities for Sec14 (relative to related Sec14-like PITPs), propose a mechanism for how NPPMs exert their inhibitory effects, and demonstrate NPPMs exhibit exquisite pathway selectivity in inhibiting phosphoinositide signaling in cells. These data deliver proof-of-concept that PITP-directed SMIs offer new and generally applicable avenues for intervening with phosphoinositide signaling pathways with selectivities superior to those afforded by contemporary lipid kinase-directed strategies. PMID:24292071

  11. Wnt signalling in gynaecological cancers: A future target for personalised medicine?

    PubMed

    Ford, C E; Henry, C; Llamosas, E; Djordjevic, A; Hacker, N

    2016-02-01

    The three major gynaecological cancers, ovarian, uterine and cervical, contribute a significant burden to global cancer mortality, and affect women in both developed and developing countries. However, unlike other cancer types that have seen rapid advances and incorporation of targeted treatments in recent years, personalised medicine is not yet a reality in the treatment of gynaecological cancers. Advances in sequencing technology and international collaborations and initiatives such as The Cancer Genome Atlas are now revealing the molecular basis of these cancers, and highlighting key signalling pathways involved. One pathway which plays a role in all three cancer types, is the Wnt signalling pathway. This complex developmental pathway is altered in most human malignancies, and members of this pathway, particularly the recently linked ROR receptor tyrosine kinases may be attractive future therapeutic targets. This review provides an up-to-date summary of research into Wnt signalling and ovarian, uterine and cervical cancers, and discusses the potential of the Wnt pathway as a future target for personalised medicine in gynaecological cancers. PMID:26432042

  12. MAPK Signaling in Cardiovascular Health and Disease: Molecular Mechanisms and Therapeutic Targets

    PubMed Central

    Muslin, Anthony J.

    2009-01-01

    Intracellular mitogen-activated protein kinase (MAPK) signaling cascades likely play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signaling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In this review, the role of the MAPKs extracellular signal-regulated kinase (ERK), C-jun N-terminal kinase (JNK) and p38 MAPK in cardiac hypertrophy, cardiac remodeling after myocardial infarction, atherosclerosis and vascular restenosis will be examined with attention paid to genetically-modified murine model systems and to the use of pharmacologic inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging. PMID:18752467

  13. Genetic/molecular alterations of meningiomas and the signaling pathways targeted

    PubMed Central

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2015-01-01

    Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features. PMID:25965831

  14. TGF-β signaling pathway as a pharmacological target in liver diseases.

    PubMed

    Zhang, Sen; Sun, Wu-Yi; Wu, Jing-Jing; Wei, Wei

    2014-07-01

    Transforming growth factor β (TGF-β) belongs to a class of pleiotropic cytokines that are involved in the processes of embryonic development, wound healing, cell proliferation, and differentiation. Moreover, TGF-β is also regarded as a central regulator in the pathogenesis and development of various liver diseases because it contributes to almost all of the stages of disease progression. A range of liver cells are considered to secrete TGF-β ligands and express related receptors and, consequently, play a crucial role in the progression of liver disease via different signal pathways. In this manuscript, we review the role of the TGF-β signaling pathway in liver disease and the potential of targeting the TGF-β signaling in the pharmacological treatment of liver diseases. PMID:24844437

  15. Signal targeting with alternating radiofrequency (STAR) sequences: application to MR angiography.

    PubMed

    Edelman, R R; Siewert, B; Adamis, M; Gaa, J; Laub, G; Wielopolski, P

    1994-02-01

    We describe a time of flight subtraction method for cine MR angiography that provides nearly perfect suppression of background signal intensity with excellent flow contrast. The method consists of a preparation phase, during which the longitudinal magnetization of the target tissue is inverted on alternate acquisitions and the background tissue is presaturated, followed by a readout phase using a cine segmented turboFLASH sequence with a shared echo modification to improve temporal resolution. With appropriate alternation of the phases of the radiofrequency excitation pulses, there is cancellation of the background signal intensity but flow signal is optimized. By using a thick section (up to 25 mm), substantial portions of the vascular territory are encompassed in a single plane. This permits rapid, dynamic assessment of flow patterns in areas such as the circle of Willis, carotid bifurcation, or renal arteries. Applications of the method for bright and dark blood cine MR angiography are demonstrated. PMID:8133761

  16. Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids.

    PubMed

    Kohnz, Rebecca A; Nomura, Daniel K

    2014-10-01

    The endocannabinoid system, most popularly known as the target of the psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), is a signaling network that modulates a diverse range of physiological processes including nociception, behavior, cognitive function, appetite, metabolism, motor control, memory formation, and inflammation. While THC and its derivatives have garnered notoriety in the eyes of the public, the endocannabinoid system consists of two endogenous signaling lipids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide), which activate cannabinoid receptors CB1 and CB2 in the nervous system and peripheral tissues. This review will focus on the recent efforts to chemically manipulate 2-AG signaling through the development of inhibitors of the 2-AG-synthesizing enzyme diacylglycerol lipase (DAGL) or the 2-AG-degrading enzyme monoacylglycerol lipase (MAGL), and assessing the therapeutic potential of DAGL and MAGL inhibitors in pain, inflammation, degenerative diseases, tissue injury, and cancer. PMID:24676249

  17. Chemokine signaling in cancer: Implications on the tumor microenvironment and therapeutic targeting

    PubMed Central

    Hembruff, Stacey L.; Cheng, Nikki

    2010-01-01

    Summary Chemokines are soluble factors shown to play important roles in regulating immune cell recruitment during inflammatory responses and defense against foreign pathogens. De-regulated expression and activity of several chemokine signaling pathways have been implicated in cancer progression, including: CCL2, CCL5, CXCL1 and CXCL12. While studies in the past have focused the role of these chemokine signaling pathways in regulating immune responses, emerging studies show that these molecules regulate diverse cellular processes including angiogenesis, and regulation of epithelial cell growth and survival. New evidence indicates that chemokines are critical for cancer progression and indicate complex and diverse functions in the tumor microenvironment. This review will focus on the contributions of chemokine signaling in regulating cancer microvironment and discuss the utility of targeting or delivering chemokines in cancer therapeutics. PMID:20651940

  18. Morelloflavone, a biflavonoid, inhibits tumor angiogenesis by targeting rho GTPases and extracellular signal-regulated kinase signaling pathways.

    PubMed

    Pang, Xiufeng; Yi, Tingfang; Yi, Zhengfang; Cho, Sung Gook; Qu, Weijing; Pinkaew, Decha; Fujise, Ken; Liu, Mingyao

    2009-01-15

    Morelloflavone, a biflavonoid extracted from Garcinia dulcis, has shown antioxidative, antiviral, and anti-inflammatory properties. However, the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date. In this study, we postulated that morelloflavone might have the ability to inhibit angiogenesis, the pivotal step in tumor growth, invasiveness, and metastasis. We showed that morelloflavone could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, and capillary-like tube formation of primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the mouse aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay. Furthermore, morelloflavone inhibited tumor growth and tumor angiogenesis of prostate cancer cells (PC-3) in xenograft mouse tumor model in vivo, suggesting that morelloflavone inhibited tumorigenesis by targeting angiogenesis. To understand the underlying mechanism of morelloflavone on the inhibitory effect of tumor growth and angiogenesis, we showed that morelloflavone could inhibit the activation of both RhoA and Rac1 GTPases but have little effect on the activation of Cdc42 GTPase. Additionally, morelloflavone inhibited the phosphorylation and activation of Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathway kinases without affecting VEGF receptor 2 activity. Together, our results indicate that morelloflavone exerts antiangiogenic action by targeting the activation of Rho-GTPases and ERK signaling pathways. These findings are the first to reveal the novel functions of morelloflavone in tumor angiogenesis and its molecular basis for the anticancer action. PMID:19147565

  19. Comparison of ganglion cell signals and psychophysical localization of moving targets can help define central motion mechanisms.

    PubMed

    Lee, Barry B; Rüttiger, Lukas; Sun, Hao

    2005-01-01

    Vernier acuity thresholds can be related to visibility of targets. This is considered in relation to retinal signals. Spatial precision of macaque ganglion cell responses to moving targets was assessed by neurometric analysis and compared with psychophysical performance. Under some conditions the amplitude of ganglion cell signals per se may relate target visibility to spatial precision of psychophysical performance. Other conditions are more complex; we suggest central mechanisms may adapt their properties, eg their dimensions, depending on the stochastic properties of ganglion cell signals. Thus, the relation of Vernier acuity to the visibility of targets is a rule of thumb which has a complex relation to physiological substrates. PMID:16178152

  20. Engineering self-contained DNA circuit for proximity recognition and localized signal amplification of target biomolecules

    PubMed Central

    Ang, Yan Shan; Yung, Lin-Yue Lanry

    2014-01-01

    Biomolecular interactions have important cellular implications, however, a simple method for the sensing of such proximal events is lacking in the current molecular toolbox. We designed a dynamic DNA circuit capable of recognizing targets in close proximity to initiate a pre-programmed signal transduction process resulting in localized signal amplification. The entire circuit was engineered to be self-contained, i.e. it can self-assemble onto individual target molecules autonomously and form localized signal with minimal cross-talk. α-thrombin was used as a model protein to evaluate the performance of the individual modules and the overall circuit for proximity interaction under physiologically relevant buffer condition. The circuit achieved good selectivity in presence of non-specific protein and interfering serum matrix and successfully detected for physiologically relevant α-thrombin concentration (50 nM–5 μM) in a single mixing step without any further washing. The formation of localized signal at the interaction site can be enhanced kinetically through the control of temperature and probe concentration. This work provides a basic general framework from which other circuit modules can be adapted for the sensing of other biomolecular or cellular interaction of interest. PMID:25056307

  1. Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

    PubMed Central

    Bruntz, Ronald C.; Lindsley, Craig W.

    2014-01-01

    Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein–coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions. PMID:25244928

  2. The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity.

    PubMed

    Slack, Cathy; Alic, Nazif; Foley, Andrea; Cabecinha, Melissa; Hoddinott, Matthew P; Partridge, Linda

    2015-07-01

    Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals. PMID:26119340

  3. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells.

    PubMed

    Ponnurangam, Sivapriya; Dandawate, Prasad R; Dhar, Animesh; Tawfik, Ossama W; Parab, Rajashri R; Mishra, Prabhu Dutt; Ranadive, Prafull; Sharma, Rajiv; Mahajan, Girish; Umar, Shahid; Weir, Scott J; Sugumar, Aravind; Jensen, Roy A; Padhye, Subhash B; Balakrishnan, Arun; Anant, Shrikant; Subramaniam, Dharmalingam

    2016-01-19

    Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1-4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins. PMID:26673007

  4. PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity

    PubMed Central

    Iwayama, Tomoaki; Steele, Cameron; Yao, Longbiao; Dozmorov, Mikhail G.; Karamichos, Dimitris; Wren, Jonathan D.

    2015-01-01

    Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFRα signaling in perivascular cells causes them to transition into ECM-synthesizing profibrotic cells. Before this transition occurs, PDGFRα signaling up-regulates mTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis. Isolated Nestin-GFP+ cells differentiate into adipocytes ex vivo and form WAT when transplanted into recipient mice. However, PDGFRα signaling opposes adipogenesis and generates profibrotic cells instead, which leads to fibrotic WAT in transplant experiments. These results identify perivascular cells as fibro/adipogenic progenitors in WAT and show that PDGFRα targets progenitor cell plasticity as a profibrotic mechanism. PMID:26019175

  5. PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity.

    PubMed

    Iwayama, Tomoaki; Steele, Cameron; Yao, Longbiao; Dozmorov, Mikhail G; Karamichos, Dimitris; Wren, Jonathan D; Olson, Lorin E

    2015-06-01

    Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFRα signaling in perivascular cells causes them to transition into ECM-synthesizing profibrotic cells. Before this transition occurs, PDGFRα signaling up-regulates mTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis. Isolated Nestin-GFP(+) cells differentiate into adipocytes ex vivo and form WAT when transplanted into recipient mice. However, PDGFRα signaling opposes adipogenesis and generates profibrotic cells instead, which leads to fibrotic WAT in transplant experiments. These results identify perivascular cells as fibro/adipogenic progenitors in WAT and show that PDGFRα targets progenitor cell plasticity as a profibrotic mechanism. PMID:26019175

  6. Ubiquitylation as a Rheostat for TCR Signaling: From Targeted Approaches Toward Global Profiling

    PubMed Central

    O’Leary, Claire E.; Lewis, Emma L.; Oliver, Paula M.

    2015-01-01

    T cell receptor (TCR) signaling must be precisely tuned to limit collateral damage and prevent reactivity to self, while still allowing robust protective immune responses that control pathogen invasion. One process that can be used to promote, modify, or terminate TCR signaling is ubiquitylation. During ubiquitylation, ubiquitin is covalently attached to target proteins through a multistep process, in which E3 ubiquitin ligases promote the formation of ubiquitin chains on selected substrates. Ubiquitylation can facilitate protein–protein interactions, direct a protein to a specific subcellular location, or initiate protein destruction. Like phosphorylation, ubiquitylation is a reversible process – deubiquitylating enzymes counteract ligase function by removing ubiquitin chains. This reversibility also allows for ubiquitin chain “editing.” Based on an emerging wealth of information from genetic loss-of-function studies showing that deregulation of ubiquitylation pathways leads to immune dysfunction, it has become increasingly apparent that the dynamic process of ubiquitylation is critical for normal immune cell function. In this review, we will describe how ubiquitylation acts as a key modulator and integrator of signaling downstream of TCR engagement. Specifically, we highlight the known roles of the substrate-specific E3 ligases and deubiquitylating enzymes in TCR signaling and T cell activation. While it is clear that ubiquitin enzymes tune T cell signaling and T cell function, elucidating the molecular mechanisms by which these proteins modulate T cells has met with significant challenges. Identifying substrates of these enzymes has been a particular challenge, and thus substrates of many E3 ligases and deubiquitylating enzymes remain largely unknown. To that end, we discuss the promise, and some practical considerations, of using proteomics-based techniques for unbiased identification of putative substrates of ubiquitin cascade proteins within

  7. Characterization, prediction and evolution of plant peroxisomal targeting signals type 1 (PTS1s).

    PubMed

    Reumann, S; Chowdhary, G; Lingner, T

    2016-05-01

    Our knowledge of the proteome of plant peroxisomes and their functional plasticity is far from being complete, primarily due to major technical challenges in experimental proteome research of the fragile cell organelle. Several unexpected novel plant peroxisome functions, for instance in biotin and phylloquinone biosynthesis, have been uncovered recently. Nevertheless, very few regulatory and membrane proteins of plant peroxisomes have been identified and functionally described up to now. To define the matrix proteome of plant peroxisomes, computational methods have emerged as important powerful tools. Novel prediction approaches of high sensitivity and specificity have been developed for peroxisome targeting signals type 1 (PTS1) and have been validated by in vivo subcellular targeting analyses and thermodynamic binding studies with the cytosolic receptor, PEX5. Accordingly, the algorithms allow the correct prediction of many novel peroxisome-targeted proteins from plant genome sequences and the discovery of additional organelle functions. In this review, we provide an overview of methodologies, capabilities and accuracies of available prediction algorithms for PTS1 carrying proteins. We also summarize and discuss recent quantitative, structural and mechanistic information of the interaction of PEX5 with PTS1 carrying proteins in relation to in vivo import efficiency. With this knowledge, we develop a model of how proteins likely evolved peroxisomal targeting signals in the past and still nowadays, in which order the two import pathways might have evolved in the ancient eukaryotic cell, and how the secondary loss of the PTS2 pathway probably happened in specific organismal groups. PMID:26772785

  8. Current and future G protein-coupled receptor signaling targets for heart failure therapy

    PubMed Central

    Siryk-Bathgate, Ashley; Dabul, Samalia; Lymperopoulos, Anastasios

    2013-01-01

    Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of β-blockers and antagonists of the renin–angiotensin–aldosterone system, this devastating disease still carries tremendous morbidity and mortality in the western world. G protein-coupled receptors, such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, ie, myocytes, fibroblasts, and endothelial cells, play crucial roles in regulation of cardiac function in health and disease. Their importance is reflected by the fact that, collectively, they represent the direct targets of over one-third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart failure therapy. Here, we review these possible targets for heart failure therapy that have emerged from studies of cardiac G protein-coupled receptor signaling in health and disease, with a particular focus on the main cardiac G protein-coupled receptor types, ie, the β-adrenergic and the angiotensin II type 1 receptors. We also highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets. PMID:24143078

  9. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

    PubMed Central

    Rimkus, Tadas K.; Carpenter, Richard L.; Qasem, Shadi; Chan, Michael; Lo, Hui-Wen

    2016-01-01

    The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials. PMID:26891329

  10. Will targeting PI3K/Akt/mTOR signaling work in hematopoietic malignancies?

    PubMed Central

    Gao, Yanan; Yuan, Chase Y.

    2016-01-01

    The constitutive activation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has been demonstrated to be critical in clinical cancer patients as well as in laboratory cancer models including hematological malignancies. Great efforts have been made to develop inhibitors targeting this pathway in hematological malignancies but so far the efficacies of these inhibitors were not as good as expected. By analyzing existing literatures and datasets available, we found that mutations of genes in the pathway only constitute a very small subset of hematological malignancies. Deep understanding of the function of gene, the pathway and/or its regulators, and the cellular response to inhibitors, may help us design better drugs targeting the hematological malignancies. PMID:27583254

  11. Signaling completion of a message transfer from an origin compute node to a target compute node

    DOEpatents

    Blocksome, Michael A.

    2011-02-15

    Signaling completion of a message transfer from an origin node to a target node includes: sending, by an origin DMA engine, an RTS message, the RTS message specifying an application message for transfer to the target node from the origin node; receiving, by the origin DMA engine, a remote get message containing a data descriptor for the message and a completion notification descriptor, the completion notification descriptor specifying a local memory FIFO data transfer operation for transferring data locally on the origin node; inserting, by the origin DMA engine in an injection FIFO buffer, the data descriptor followed by the completion notification descriptor; transferring, by the origin DMA engine to the target node, the message in dependence upon the data descriptor; and notifying, by the origin DMA engine, the application that transfer of the message is complete in dependence upon the completion notification descriptor.

  12. Signaling completion of a message transfer from an origin compute node to a target compute node

    DOEpatents

    Blocksome, Michael A.; Parker, Jeffrey J.

    2011-05-24

    Signaling completion of a message transfer from an origin node to a target node includes: sending, by an origin DMA engine, an RTS message, the RTS message specifying an application message for transfer to the target node from the origin node; receiving, by the origin DMA engine, a remote get message containing a data descriptor for the message and a completion notification descriptor, the completion notification descriptor specifying a local direct put transfer operation for transferring data locally on the origin node; inserting, by the origin DMA engine in an injection FIFO buffer, the data descriptor followed by the completion notification descriptor; transferring, by the origin DMA engine to the target node, the message in dependence upon the data descriptor; and notifying, by the origin DMA engine, the application that transfer of the message is complete in dependence upon the completion notification descriptor.

  13. Monodisperse magnetite nanoparticles coupled with nuclear localization signal peptide for cell-nucleus targeting.

    PubMed

    Xu, Chenjie; Xie, Jin; Kohler, Nathan; Walsh, Edward G; Chin, Y Eugene; Sun, Shouheng

    2008-03-01

    Functionalization of monodisperse superparamagnetic magnetite (Fe(3)O(4)) nanoparticles for cell specific targeting is crucial for cancer diagnostics and therapeutics. Targeted magnetic nanoparticles can be used to enhance the tissue contrast in magnetic resonance imaging (MRI), to improve the efficiency in anticancer drug delivery, and to eliminate tumor cells by magnetic fluid hyperthermia. Herein we report the nucleus-targeting Fe(3)O(4) nanoparticles functionalized with protein and nuclear localization signal (NLS) peptide. These NLS-coated nanoparticles were introduced into the HeLa cell cytoplasm and nucleus, where the particles were monodispersed and non-aggregated. The success of labeling was examined and identified by fluorescence microscopy and MRI. The work demonstrates that monodisperse magnetic nanoparticles can be readily functionalized and stabilized for potential diagnostic and therapeutic applications. PMID:18080259

  14. USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

    PubMed Central

    Herhaus, Lina; Al-Salihi, Mazin A.; Dingwell, Kevin S.; Cummins, Timothy D.; Wasmus, Lize; Vogt, Janis; Ewan, Richard; Bruce, David; Macartney, Thomas; Weidlich, Simone; Smith, James C.; Sapkota, Gopal P.

    2014-01-01

    Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis. PMID:24850914

  15. A simple colorimetric DNA detection by target-induced hybridization chain reaction for isothermal signal amplification.

    PubMed

    Ma, Cuiping; Wang, Wenshuo; Mulchandani, Ashok; Shi, Chao

    2014-07-15

    A novel DNA detection method is presented based on a gold nanoparticle (AuNP) colorimetric assay and hybridization chain reaction (HCR). In this method, target DNA hybridized with probe DNA modified on AuNP, and triggered HCR. The resulting HCR products with a large number of negative charges significantly enhanced the stability of AuNPs, inhibiting aggregation of AuNPs at an elevated salt concentration. The approach was highly sensitive and selective. Using this enzyme-free and isothermal signal amplification method, we were able to detect target DNA at concentrations as low as 0.5 nM with the naked eye. Our method also has great potential for detecting other analytes, such as metal ions, proteins, and small molecules, if the target analytes could make HCR products attach to AuNPs. PMID:24780220

  16. Redox Signaling as a Therapeutic Target to Inhibit Myofibroblast Activation in Degenerative Fibrotic Disease

    PubMed Central

    Berger, Peter; Zenzmaier, Christoph

    2014-01-01

    Degenerative fibrotic diseases encompass numerous systemic and organ-specific disorders. Despite their associated significant morbidity and mortality, there is currently no effective antifibrotic treatment. Fibrosis is characterized by the development and persistence of myofibroblasts, whose unregulated deposition of extracellular matrix components disrupts signaling cascades and normal tissue architecture leading to organ failure and death. The profibrotic cytokine transforming growth factor beta (TGFβ) is considered the foremost inducer of fibrosis, driving myofibroblast differentiation in diverse tissues. This review summarizes recent in vitro and in vivo data demonstrating that TGFβ-induced myofibroblast differentiation is driven by a prooxidant shift in redox homeostasis. Elevated NADPH oxidase 4 (NOX4)-derived hydrogen peroxide (H2O2) supported by concomitant decreases in nitric oxide (NO) signaling and reactive oxygen species scavengers are central factors in the molecular pathogenesis of fibrosis in numerous tissues and organs. Moreover, complex interplay between NOX4-derived H2O2 and NO signaling regulates myofibroblast differentiation. Restoring redox homeostasis via antioxidants or NOX4 inactivation as well as by enhancing NO signaling via activation of soluble guanylyl cyclases or inhibition of phosphodiesterases can inhibit and reverse myofibroblast differentiation. Thus, dysregulated redox signaling represents a potential therapeutic target for the treatment of wide variety of different degenerative fibrotic disorders. PMID:24701562

  17. Differential Signaling by Protease-Activated Receptors: Implications for Therapeutic Targeting

    PubMed Central

    Sidhu, Tejminder S.; French, Shauna L.; Hamilton, Justin R.

    2014-01-01

    Protease-activated receptors (PARs) are a family of four G protein-coupled receptors that exhibit increasingly appreciated differences in signaling and regulation both within and between the receptor class. By nature of their proteolytic self-activation mechanism, PARs have unique processes of receptor activation, “ligand” binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit—the most notable example of which is inhibition of PAR1 on platelets for the prevention of arterial thrombosis. However, more recent studies have uncovered further distinguishing features of PAR-mediated signaling, revealing mechanisms by which identical proteases elicit distinct effects in the same cell, as well as how distinct proteases produce different cellular consequences via the same receptor. Here we review this differential signaling by PARs, highlight how important distinctions between PAR1 and PAR4 are impacting on the progress of a new class of anti-thrombotic drugs, and discuss how these more recent insights into PAR signaling may present further opportunities for manipulating PAR activation and signaling in the development of novel therapies. PMID:24733067

  18. WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals

    PubMed Central

    Kann, Martin; Bae, Eunnyung; Lenz, Maximilian O.; Li, Liangji; Trannguyen, BaoTran; Schumacher, Valerie A.; Taglienti, Mary E.; Bordeianou, Liliana; Hartwig, Sunny; Rinschen, Markus M.; Schermer, Bernhard; Benzing, Thomas; Fan, Chen-Ming; Kreidberg, Jordan A.

    2015-01-01

    Development of the metanephric kidney depends on tightly regulated interplay between self-renewal and differentiation of a nephron progenitor cell (NPC) pool. Several key factors required for the survival of NPCs have been identified, including fibroblast growth factor (FGF) signaling and the transcription factor Wilms' tumor suppressor 1 (WT1). Here, we present evidence that WT1 modulates FGF signaling by activating the expression of growth arrest-specific 1 (Gas1), a novel WT1 target gene and novel modulator of FGF signaling. We show that WT1 directly binds to a conserved DNA binding motif within the Gas1 promoter and activates Gas1 mRNA transcription in NPCs. We confirm that WT1 is required for Gas1 expression in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. Although kidney development in Gas1 knockout mice progresses normally until E15.5, NPCs show decreased rates of proliferation at this stage and are depleted as of E17.5. Lastly, we show that Gas1 is selectively required for FGF-stimulated AKT signaling in vitro. In summary, our data suggest a model in which WT1 modulates receptor tyrosine kinase signaling in NPCs by directing the expression of Gas1. PMID:25804736

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

    PubMed Central

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

    2011-01-01

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

  20. Three-dimensional analysis of moving target radar signals: methods and implications for ATR and feature-aided tracking

    NASA Astrophysics Data System (ADS)

    Stuff, Mark A.

    1999-08-01

    Like the hypothetical shadow watchers of Plato's cave, ATR researchers have spent years in the study of one and two- dimensional signals, collected from three dimensional targets. Three-dimensional geometric invariance theory of radar returns from moving targets gives us a new opportunity to escape the study of two-dimensional information which is present, with probability one, in the signals from any randomly moving target. Target recognition for moving targets is fundamentally harder than for stationary targets, if one remains in a two- dimensional paradigm. Viewing geometry calculations based on sensor flight lines become false, due to uncontrolled target rotations. Three-dimensional analysis shows that even the most optimal purely two-dimensional approach will generically construct false target measurements and distorted target images. But the geometric facts also show that all types of three-dimensional Euclidean invariants, such as true (not projected) lengths, surface areas, angles, and volumes of target components can be extracted from moving target data. These facts have profound implications for target recognition, and for the dynamic tracking of target movements, allowing target signals to be correlated by comparing fundamental three-dimensional invariants, which are not confounded by changing illumination directions.

  1. Functional signaling pathway analysis of lung adenocarcinomas identifies novel therapeutic targets for KRAS mutant tumors.

    PubMed

    Baldelli, Elisa; Bellezza, Guido; Haura, Eric B; Crinó, Lucio; Cress, W Douglas; Deng, Jianghong; Ludovini, Vienna; Sidoni, Angelo; Schabath, Matthew B; Puma, Francesco; Vannucci, Jacopo; Siggillino, Annamaria; Liotta, Lance A; Petricoin, Emanuel F; Pierobon, Mariaelena

    2015-10-20

    Little is known about the complex signaling architecture of KRAS and the interconnected RAS-driven protein-protein interactions, especially as it occurs in human clinical specimens. This study explored the activated and interconnected signaling network of KRAS mutant lung adenocarcinomas (AD) to identify novel therapeutic targets.Thirty-four KRAS mutant (MT) and twenty-four KRAS wild-type (WT) frozen biospecimens were obtained from surgically treated lung ADs. Samples were subjected to Laser Capture Microdissection and Reverse Phase Protein Microarray analysis to explore the expression/activation levels of 150 signaling proteins along with co-activation concordance mapping. An independent set of 90 non-small cell lung cancers (NSCLC) was used to validate selected findings by immunohistochemistry (IHC).Compared to KRAS WT tumors, the signaling architecture of KRAS MT ADs revealed significant interactions between KRAS downstream substrates, the AKT/mTOR pathway, and a number of Receptor Tyrosine Kinases (RTK). Approximately one-third of the KRAS MT tumors had ERK activation greater than the WT counterpart (p<0.01). Notably 18% of the KRAS MT tumors had elevated activation of the Estrogen Receptor alpha (ER-α) (p=0.02).This finding was verified in an independent population by IHC (p=0.03).KRAS MT lung ADs appear to have a more intricate RAS linked signaling network than WT tumors with linkage to many RTKs and to the AKT-mTOR pathway. Combination therapy targeting different nodes of this network may be necessary to treat this group of patients. In addition, for patients with KRAS MT tumors and activation of the ER-α, anti-estrogen therapy may have important clinical implications. PMID:26468985

  2. Functional signaling pathway analysis of lung adenocarcinomas identifies novel therapeutic targets for KRAS mutant tumors

    PubMed Central

    Baldelli, Elisa; Bellezza, Guido; Haura, Eric B.; Crinó, Lucio; Cress, W. Douglas; Deng, Jianghong; Ludovini, Vienna; Sidoni, Angelo; Schabath, Matthew B.; Puma, Francesco; Vannucci, Jacopo; Siggillino, Annamaria; Liotta, Lance A.; Petricoin, Emanuel F.; Pierobon, Mariaelena

    2015-01-01

    Little is known about the complex signaling architecture of KRAS and the interconnected RAS-driven protein-protein interactions, especially as it occurs in human clinical specimens. This study explored the activated and interconnected signaling network of KRAS mutant lung adenocarcinomas (AD) to identify novel therapeutic targets. Thirty-four KRAS mutant (MT) and twenty-four KRAS wild-type (WT) frozen biospecimens were obtained from surgically treated lung ADs. Samples were subjected to laser capture microdissection and reverse phase protein microarray analysis to explore the expression/activation levels of 150 signaling proteins along with co-activation concordance mapping. An independent set of 90 non-small cell lung cancers (NSCLC) was used to validate selected findings by immunohistochemistry (IHC). Compared to KRAS WT tumors, the signaling architecture of KRAS MT ADs revealed significant interactions between KRAS downstream substrates, the AKT/mTOR pathway, and a number of Receptor Tyrosine Kinases (RTK). Approximately one-third of the KRAS MT tumors had ERK activation greater than the WT counterpart (p<0.01). Notably 18% of the KRAS MT tumors had elevated activation of the Estrogen Receptor alpha (ER-α) (p=0.02). This finding was verified in an independent population by IHC (p=0.03). KRAS MT lung ADs appear to have a more intricate RAS linked signaling network than WT tumors with linkage to many RTKs and to the AKT-mTOR pathway. Combination therapy targeting different nodes of this network may be necessary to treat this group of patients. In addition, for patients with KRAS MT tumors and activation of the ER-α, anti-estrogen therapy may have important clinical implications. PMID:26468985

  3. Detection and tracking of humans and vehicle targets using high definition television signals in urban areas

    NASA Astrophysics Data System (ADS)

    Greneker, Gene

    2007-04-01

    The detection and tracking of humans and vehicles on the battlefield using radar systems operating at microwave frequencies was first achieved almost 40 years ago. The subsequent generation of radars designed to detect personnel and vehicles on the battlefield has seen improvements due to increased signal processing capability. To date, most of the self-contained human detection radars have incorporated a co-located (monostatic) transmitter and receiver operated by humans. Approximately, three decades ago the bistatic radar was introduced and used for security at high value target sites. These bistatic "fence" radars employ a transmitter located at one end of a bistatic baseline and a receiver at the other end of the baseline. The receiver is tuned to the transmitter. Operation is simple; an intruder crosses the bistatic baseline and is detected after simple signal processing is performed on the bistatic signature produced by the intruder. The experiments demonstrate that passive bistatic radar can be used to detect humans and vehicles. This paper describes "quick-look" experiments that have been conducted in the Atlanta, Georgia area to detect humans and vehicles using a passive radar configuration requiring no coordination between the receiver and transmitter. The illumination source (transmitter) is a High Definition Television (HDTV) broadcast transmitter located approximately 13.5 miles from the test area. The transmitter is broadcasting a 6 MHz wide digital signal with a pilot carrier on a frequency of 548.310 MHz. The continuous wave (CW) pilot carrier HDTV signal component is processed to extract the signature of the walking human or the signature of a vehicle. The experimental receiving system utilizes a commercial off-the-shelf (COTS) communications receiver. A set of multi-element back to back Yagi antennas are used to provide a reference signal and the signal from the area where the human subject is located. The walking human generates micro

  4. Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference.

    PubMed

    Biel, Nikolett M; Siemann, Dietmar W

    2016-10-01

    Anti-angiogenic therapies target the tumor vasculature, impairing its development and growth. It was hypothesized over 40 years ago by the late Judah Folkman and Julie Denekamp that depriving a tumor of oxygen and nutrients, by targeting the tumor vasculature, could have therapeutic benefits. Identification of growth factors and signaling pathways important in angiogenesis subsequently led to the development of a series of anti-angiogenic agents that over the past decade have become part of the standard of care in several disease settings. Unfortunately not all patients respond to the currently available anti-angiogenic therapies while others become resistant to these agents following prolonged exposure. Identification of new pathways that may drive angiogenesis led to the development of second-generation anti-angiogenic agents such as those targeting the Ang-2/Tie2 axis. Recently, it has become clear that combination of first and second generation agents targeting the blood vessel network can lead to outcomes superior to those using either agent alone. The present review focuses on the current status of VEGF and Ang-2 targeted agents and the potential utility of using them in combination to impair tumor angiogenesis. PMID:25312939

  5. Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference

    PubMed Central

    Biel, Nikolett M.; Siemann, Dietmar W.

    2014-01-01

    Anti-angiogenic therapies target the tumor vasculature, impairing its development and growth. It was hypothesized over 40 years ago by the late Judah Folkman and Julie Denekamp that depriving a tumor of oxygen and nutrients, by targeting the tumor vasculature, could have therapeutic benefits. Identification of growth factors and signaling pathways important in angiogenesis subsequently led to the development of a series of anti-angiogenic agents that over the past decade have become part of the standard of care in several disease settings. Unfortunately not all patients respond to the currently available anti-angiogenic therapies while others become resistant to these agents following prolonged exposure. Identification of new pathways that may drive angiogenesis led to the development of second-generation anti-angiogenic agents such as those targeting the Ang-2/Tie2 axis. Recently, it has become clear that combination of first and second generation agents targeting the blood vessel network can lead to outcomes superior to those using either agent alone. The present review focuses on the current status of VEGF and Ang-2 targeted agents and the potential utility of using them in combination to impair tumor angiogenesis. PMID:25312939

  6. Resistance of Cancer Cells to Targeted Therapies Through the Activation of Compensating Signaling Loops.

    PubMed

    von Manstein, Viktoria; Yang, Chul Min; Richter, Diane; Delis, Natalia; Vafaizadeh, Vida; Groner, Bernd

    2013-12-01

    The emergence of low molecular weight kinase inhibitors as "targeted" drugs has led to remarkable advances in the treatment of cancer patients. The clinical benefits of these tumor therapies, however, vary widely in patient populations and with duration of treatment. Intrinsic and acquired resistance against such drugs limits their efficacy. In addition to the well studied mechanisms of resistance based upon drug transport and metabolism, genetic alterations in drug target structures and the activation of compensatory cell signaling have received recent attention. Adaptive responses can be triggered which counteract the initial dependence of tumor cells upon a particular signaling molecule and allow only a transient inhibition of tumor cell growth. These compensating signaling mechanisms are often based upon the relief of repression of regulatory feedback loops. They might involve cell autonomous, intracellular events or they can be mediated via the secretion of growth factor receptor ligands into the tumor microenvironment and signal induction in an auto- or paracrine fashion. The transcription factors Stat3 and Stat5 mediate the biological functions of cytokines, interleukins and growth factors and can be considered as endpoints of multiple signaling pathways. In normal cells this activation is transient and the Stat molecules return to their non-phosphorylated state within a short time period. In tumor cells the balance between activating and de-activating signals is disturbed resulting in the persistent activation of Stat3 or Stat5. The constant activation of Stat3 induces the expression of target genes, which cause the proliferation and survival of cancer cells, as well as their migration and invasive behavior. Activating components of the Jak-Stat pathway have been recognized as potentially valuable drug targets and important principles of compensatory signaling circuit induction during targeted drug treatment have been discovered in the context of kinase

  7. SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

    PubMed Central

    Popovic, Jelena; Schwirtlich, Marija; Rankovic, Branislava; Stevanovic, Milena

    2015-01-01

    Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation. PMID:26588701

  8. Redox modulation of cellular metabolism through targeted degradation of signaling proteins by the proteasome

    SciTech Connect

    Squier, Thomas C.

    2006-02-01

    Under conditions of oxidative stress, the 20S proteasome plays a critical role in maintaining cellular homeostasis through the selective degradation of oxidized and damaged proteins. This adaptive stress response is distinct from ubiquitin-dependent pathways in that oxidized proteins are recognized and degraded in an ATP-independent mechanism, which can involve the molecular chaperone Hsp90. Like the regulatory complexes 19S and 11S REG, Hsp90 tightly associates with the 20S proteasome to mediate the recognition of aberrant proteins for degradation. In the case of the calcium signaling protein calmodulin, proteasomal degradation results from the oxidation of a single surface exposed methionine (i.e., Met145); oxidation of the other eight methionines has a minimal effect on the recognition and degradation of calmodulin by the proteasome. Since cellular concentrations of calmodulin are limiting, the targeted degradation of this critical signaling protein under conditions of oxidative stress will result in the downregulation of cellular metabolism, serving as a feedback regulation to diminish the generation of reactive oxygen species. The targeted degradation of critical signaling proteins, such as calmodulin, can function as sensors of oxidative stress to downregulate global rates of metabolism and enhance cellular survival.

  9. Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation.

    PubMed

    Zhao, Yang; Zhao, Ming-Ming; Cai, Yan; Zheng, Ming-Fei; Sun, Wei-Liang; Zhang, Song-Yang; Kong, Wei; Gu, Jun; Wang, Xian; Xu, Ming-Jiang

    2015-10-01

    Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis. Interestingly, the expression of Klotho, an antiaging gene that suppresses VC, was reduced in calcified vasculature, whereas rapamycin reversed membrane and secreted Klotho decline through mTOR inhibition. When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate-treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression. More importantly, rapamycin failed to reduce VC in the absence of Klotho by using either siRNA knockdown of Klotho or Klotho knockout mice. Thus, Klotho has a critical role in mediating the observed decrease in calcification by rapamycin in vitro and in vivo. PMID:26061549

  10. Dissecting the PI3K Signaling Axis in Pediatric Solid Tumors: Novel Targets for Clinical Integration

    PubMed Central

    Loh, Amos H. P.; Brennan, Rachel C.; Lang, Walter H.; Hickey, Robert J.; Malkas, Linda H.; Sandoval, John A.

    2013-01-01

    Children with solid tumors represent a unique population. Recent improvements in pediatric solid tumor survival rates have been confined to low- and moderate-risk cancers, whereas minimal to no notable improvement in survival have been observed in high-risk and advanced-stage childhood tumors. Treatments for patients with advanced disease are rarely curative, and responses to therapy are often followed by relapse, which highlights the large unmet need for novel therapies. Recent advances in cancer treatment have focused on personalized therapy, whereby patients are treated with agents that best target the molecular drivers of their disease. Thus, a better understanding of the pathways that drive cancer or drug resistance is of critical importance. One such example is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which is activated in many solid cancer patients and represents a target for therapy. PI3K/Akt/mTOR pathway activation has also been observed in tumors resistant to agents targeting upstream receptor tyrosine kinases (RTKs). Agents that target this pathway have the potential to shut down survival pathways, and are being explored both in the setting of pathway-activating mutations and for their ability to restore sensitivity to upstream signaling targeted agents. Here, we examine the role of the PI3K/Akt/mTOR pathway in pediatric solid tumors, review the novel agents being explored to target this pathway, and explore the potential role of the inhibition of this pathway in the clinical development of these agents in children. PMID:23638435