Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of in vitro models for testicular toxicity may provide important tools for investigating specific mechanisms of toxicity in the testis. Although various systems have been reported, their application in toxicological studies has been limited by the poor ability to replicate the complex biochemical, molecular, and functional interactions observed in the testis. In the present study, we evaluated a significantly improved Sertoli cell/gonocyte co-culture (SGC) system that employs a 3-dimensional extracellular matrix Matrigel (ECM) applied as an overlay instead of a substratum. We explored the dose- and time-dependent effects of the addition of such an ECM overlay on cytoskeletal and morphological changes in the SGC system, and the resulting effects on cellular integrity. Furthermore, we correlated the latter effects with the ECM-dependent modulation of stress and survival signaling pathways and, most critically, the expression levels of the spermatogonia-specific protein, c-Kit. Finally, we applied this co-culture system to investigate the dose- and time-dependent effects on the morphology and induction of apoptosis of cadmium. We observed that the dose-dependent addition of an ECM overlay led to an enhanced attachment of Sertoli cells and facilitated the establishment of SGC communication and cytoskeletal structure, with a dramatic improvement in cell viability. The latter was consistent with the observed dose- and time-dependent modulation of both stress signaling pathways (SAPK/JNK) and survival signaling pathways (ERK and AKT) in the presence of the ECM overlay. Furthermore, the dose-dependent stabilization of c-Kit protein expression confirmed the functional integrity of this co-culture system. We conclude that this modified SGC system will provide investigators with a simple, efficient, and highly reproducible alternative in the screen for testicular cell-specific cytotoxicity and the assessment of molecular mechanisms associated with both normal development and reproductive toxicity induced by environmental toxicants.
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PMID:Essential role of extracellular matrix (ECM) overlay in establishing the functional integrity of primary neonatal rat Sertoli cell/gonocyte co-cultures: an improved in vitro model for assessment of male reproductive toxicity. 1565 72

The Ras-Raf-MEK-ERK (ERK) pathway is a logical therapeutic target because it represents a common downstream pathway for several key growth factor tyrosine kinase receptors which are often mutated or overexpressed in human cancers. Although considered mainly growth-promoting, in certain contexts, this pathway also seems to be apoptosis-suppressing. Several novel agents targeting this pathway have now been developed and are in clinical trials. One of the most interesting new agents is BAY 43-9006. Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties. To date, encouraging results have been seen with BAY 43-9006, particularly in renal cell cancers which are highly vascular tumors. This review will provide an overview of the ERK signaling pathway in normal and neoplastic tissue, with a specific focus on novel therapies targeting the ERK pathway at the level of Raf kinase.
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PMID:Raf kinase as a target for anticancer therapeutics. 1582 42

Stem cell factor (SCF) is a highly expressed cytokine in the central nervous system. In the present study, we demonstrate a neuroprotective role for SCF and its tyrosine kinase receptor, c-kit, against camptothecin-induced apoptosis and glutamate excitotoxicity in rat cortical neurons. This protection was blocked by pharmacological or molecular inhibition of either the MEK/ERK or PI3K/Akt signaling pathways. The importance of these pathways was further confirmed by the activation of both ERK, in a MEK-dependent manner, and Akt, via PI3K. Activation of Akt increased the binding of the p50 and p65 subunits of NFkappaB, which was also important for neuroprotection. Akt inhibition prevented NFkappaB binding, suggesting a role for Akt in SCF-induced NFkappaB. Pharmacological inhibition of NFkappaB or dominant negative IkappaB also prevented neuroprotection by SCF. SCF up-regulated the anti-apoptotic genes, bcl-2 and bcl-xL in an NFkappaB-dependent manner. Together, these findings demonstrate a neuroprotective role for SCF in cortical neurons, an effect that was mediated by Akt and ERK, as well as NFkappaB-mediated gene transcription. SCF represents a novel therapeutic target in the treatment of neurodegenerative disease.
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PMID:Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFkappaB. 1618 9

Tyrosine kinases have been strongly implicated as therapeutic targets that influence the angiogenic process in growing tumors. In this study, we revealed that TKI-31 is a potent broad spectrum tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor beta (PDGFRbeta) and also inhibits kinases of other class, such as c-Kit and c-Src on molecular base, but showed no activity against vascular endothelial growth factor receptor 1 (VEGFR1) and epidermal growth factor receptor (EGFR). TKI-31 inhibits VEGF-induced phosphorylation of VEGFR2 in endothelial cells as well as PDGF(BB)-induced phosphorylation in fibroblast cells, and leading to the inhibition of down-stream signaling triggered by these receptors such as PI3K/Akt/mTOR, MAPK42/44(ERK) and paxillin. TKI-31 also inhibited VEGF-induced endothelial cells proliferation, migration and their differentiation into capillary-like tube formation. Its anti-angiogenic property was further confirmed by the inhibition of neovascularization on CAM, in vivo. These results collectively highlight the therapeutic potential of this compound for the treatment of solid tumors and other diseases where angiogenesis plays an important role.
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PMID:TKI-31 inhibits angiogenesis by combined suppression signaling pathway of VEGFR2 and PDGFRbeta. 1657 1

Reactive mastocytosis (RM) in epithelial surfaces is a consistent Th2-associated feature of allergic disease. RM fails to develop in mice lacking leukotriene (LT) C4 synthase (LTC4S), which is required for cysteinyl leukotriene (cys-LT) production. We now report that IL-4, which induces LTC4S expression by mast cells (MCs), requires cys-LTs, the cys-LT type 1 receptor (CysLT1), and Gi proteins to promote MC proliferation. LTD4 (10-1000 nM) enhanced proliferation of human MCs in a CysLT1-dependent, pertussis toxin-sensitive manner. LTD4-induced phosphorylation of ERK required transactivation of c-kit. IL-4-driven comitogenesis was likewise sensitive to pertussis toxin or a CysLT1-selective antagonist and was attenuated by treatment with leukotriene synthesis inhibitors. Mouse MCs lacking LTC4S or CysLT1 showed substantially diminished IL-4-induced comitogenesis. Thus, IL-4 induces proliferation in part by inducing LTC4S and cys-LT generation, which causes CysLT1 to transactivate c-kit in RM.
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PMID:Cutting edge: Interleukin 4-dependent mast cell proliferation requires autocrine/intracrine cysteinyl leukotriene-induced signaling. 1692 Sep 8

Defining how cancer-associated mutations perturb signaling networks in stem/progenitor populations that are integral to tumor formation and maintenance is a fundamental problem with biologic and clinical implications. Point mutations in RAS genes contribute to many cancers, including myeloid malignancies. We investigated the effects of an oncogenic Kras(G12D) allele on phosphorylated signaling molecules in primary c-kit(+) lin(-/low) hematopoietic stem/progenitor cells. Comparison of wild-type and Kras(G12D) c-kit(+) lin(-/low) cells shows that K-Ras(G12D) expression causes hyperproliferation in vivo and results in abnormal levels of phosphorylated STAT5, ERK, and S6 under basal and stimulated conditions. Whereas Kras(G12D) cells demonstrate hyperactive signaling after exposure to granulocyte-macrophage colony-stimulating factor, we unexpectedly observe a paradoxical attenuation of ERK and S6 phosphorylation in response to stem cell factor. These studies provide direct biochemical evidence that cancer stem/progenitor cells remodel signaling networks in response to oncogenic stress and demonstrate that multi-parameter flow cytometry can be used to monitor the effects of targeted therapeutics in vivo. This strategy has broad implications for defining the architecture of signaling networks in primary cancer cells and for implementing stem cell-targeted interventions.
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PMID:K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. 1719 89

Previously, we demonstrated that c-kit and stem cell factors (SCF) commonly co-expressed in primary and metastatic nasopharyngeal carcinomas (NPC), and in HONE-1 NPC cells with tyrosine autophosphorylation of c-kit. These findings suggest that the SCF/c-kit signaling may contribute to pathogenesis of NPC. Therefore, the efficacy of STI571 treatment alone and when combined with cisplatin on HONE-1 cells were evaluated. STI571 induced growth inhibition at the IC50 concentration (14.9 microM). When the concentration was at or higher than 30 microM, the induction of cell apoptosis was observed. The effects of STI571 were shown to be mediated by the sustained activation of ERK but did not involve the inhibition of c-kit signal activity. When the STI571 (5 microM) and cisplatin (5 microg/ml) treatments were combined, there were further inductions of ERK activation resulting in obviously enhanced growth inhibition and induction of cell apoptosis. In a xenograft model, STI571 (50 mg/kg/day) showed only a limited ability to inhibit HONE-1 cell growth, but when combined with cisplatin (3 mg/kg/twice a week) treatment, there was a significant improvement in growth inhibition compared with STI571 or cisplatin treatment alone. Our results provide experimental support for the advanced NPC therapeutic trials using the combined STI571 and cisplatin treatment.
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PMID:STI571 sensitizes nasopharyngeal carcinoma cells to cisplatin: sustained activation of ERK with improved growth inhibition. 1720 22

Using a Transwell chamber as migration assay for mouse primordial germ cells (PGCs), we show here that these cells posses directional migration in the absence of somatic cell and defined matrix support and in response to a Kit ligand (KL) gradient or medium conditioned by Aorta/Gonad/Mesonephros and gonadal ridges. Other putative PGC chemoattractants such as SDF1 and TGFbeta did not exert any attractive action on PGCs. The chemoattractant activity of KL and conditioned medium was also evidenced by their ability to stimulate actin reorganization in PGCs. In the aim to identify downstream signaling pathways governing KL chemoattraction on PGCs, we demonstrated that in such cells KL rapidly (5 min) increased autophosphorylation of its receptor c-Kit and caused phosphorylation of the serine-threonine kinase AKT through the action of PI3K. 740Y-P peptide, a direct activator of PI3 kinase, stimulated PGC migration at levels similar to those elicited by KL. LY294002 (a specific inhibitor of PI3K) abolished KL-dependent PGC migration or the chemoattractant activity of the conditioned medium and inhibited AKT phosphorylation; Src kinase inhibitors PP2 and SU6656, caused significant reduction of the KL-dependent PGC migration and AKT phosphorylation, while U0126, a selective inhibitor of the MEK/ERK protein kinase cascade, reduced PGC migration and AKT phosphorylation at lesser extent. SU6656 completely abolished the chemoattractant activity of the conditioned medium. Finally, SB202190 (a p38 inhibitor) and rapamycin (mTOR inhibitor) did not affect PGC migration. In addition, to demonstrate that somatic cells are not essential for PGC motility and directional migration, we evidenced a novel role for KL as PGC chemoattractant and for PI3K/AKT and Src kinase, as players involved in the activation of the PGC migratory machinery and likely important for their directional movement towards the gonadal ridges.
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PMID:Chemoattractant action and molecular signaling pathways of Kit ligand on mouse primordial germ cells. 1746 86

It is well known that c-kit is related to pigmentation as well as to the oncology target protein. The objective of this study was to discover a skin-whitening agent that regulates c-kit activity. We have developed a high-throughput screening system using recombinant human c-kit protein. Approximately 10,000 synthetic compounds were screened for their effect on c-kit activity. Phenyl-imidazole sulfonamide derivatives showed inhibitory activity on c-kit phosphorylation in vitro. The effects of one derivative, [4-t-butylphenyl]-N-(4-imidazol-1-yl phenyl)sulfonamide (ISCK03), on stem-cell factor (SCF)/c-kit cellular signaling in 501mel human melanoma cells were examined further. Pretreatment of 501mel cells with ISCK03 inhibited SCF-induced c-kit phosphorylation dose dependently. ISCK03 also inhibited p44/42 ERK mitogen-activated protein kinase (MAPK) phosphorylation, which is known to be involved in SCF/c-kit downstream signaling. However ISCK03 did not inhibit hepatocyte growth factor (HGF)-induced phosphorylation of p44/42 ERK proteins. To determine the in vivo potency of ISCK03, it was orally administered to depilated C57BL/6 mice. Interestingly, oral administration of ISCK03 induced the dose-dependent depigmentation of newly regrown hair, and this was reversed with cessation of ISCK03 treatment. Finally, to investigate whether the inhibitory effect of ISCK03 on SCF/c-kit signaling abolished UV-induced pigmentation, ISCK03 was applied to UV-induced pigmented spots on brownish guinea pig skin. The topical application of ISCK03 promoted the depigmentation of UV-induced hyperpigmented spots. Fontana-Masson staining analysis showed epidermal melanin was diminished in spots treated with ISCK03. These results indicate that phenyl-imidazole sulfonamide derivatives are potent c-kit inhibitors and might be used as skin-whitening agents.
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PMID:[4-t-butylphenyl]-N-(4-imidazol-1-yl phenyl)sulfonamide (ISCK03) inhibits SCF/c-kit signaling in 501mel human melanoma cells and abolishes melanin production in mice and brownish guinea pigs. 1765 83

Spreds form a new protein family with an N-terminal Enabled/VASP homology 1 domain (EVH1), a central c-Kit binding domain (KBD) and a C-terminal Sprouty-related domain (SPR). They are able to inhibit the Ras-ERK signalling pathway after various mitogenic stimulations. In mice, Spred proteins are identified as regulators of bone morphogenesis, hematopoietic processes, allergen-induced airway eosinophilia and hyperresponsiveness. They inhibit cell motility and metastasis and have a high potential as tumor markers and suppressors of carcinogenesis. Moreover, in vertebrates, XtSpreds help together with XtSprouty proteins to coordinate gastrulation and mesoderm specification. Here, we give an overview of this new field and summarize the domain functions, binding partners, expression patterns and the cellular localizations, regulations and functions of Spred proteins and try to give perspectives for future scientific directions.
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PMID:Getting a first clue about SPRED functions. 1769 Nov 6


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