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)

Products of the ras gene family, termed p21ras, are GTP-binding proteins that have been implicated in signal transduction via receptors encoding tyrosine kinase domains. Recent findings have defined a superfamily of hemopoietin receptors that includes receptors for a number of interleukins and colony-stimulating factors. The intracellular portions of these receptors show only restricted homologies, have no tyrosine kinase domain, and provide no clues to the mode of signal transduction. However, in most cases the factors stimulate tyrosine phosphorylation. We demonstrate here that ligand-induced activation of the interleukin (IL)-2, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors resulted in activation of p21ras in various hemopoietic cell lines. The only cytokine tested that binds to a hemopoietin receptor and that did not activate p21ras was IL-4. Activation of p21ras was also observed in response to Steel factor, which stimulates the endogenous tyrosine kinase activity of the c-kit receptor, as well as with phorbol esters, which activate protein kinase C. Experiments with protein kinase inhibitors implicated tyrosine kinase activity, but not protein kinase C activity, as the upstream signal in p21ras activation via these growth factor receptors. Attempts to demonstrate tyrosine phosphorylation of the p21ras GTPase-activating protein (GAP) were negative, suggesting that phosphorylation of GAP may not be the major mechanism for regulation of p21ras activity by tyrosine kinases.
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PMID:p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. 137 79

Enforced expression of p210bcr-abl transforms interleukin 3 (IL-3)-dependent hematopoietic cell lines to growth factor-independent proliferation. It has been demonstrated that nonreceptor tyrosine kinase oncogenes may couple to the p21ras pathway to exert their transforming effect. In particular, p210bcr-abl was recently found to effect p21ras activation in hematopoietic cells. In this context, experiments were performed to evaluate a protein signaling pathway by which p210bcr-abl might regulate p21ras. It was asked whether Shc p46/p52, a protein containing a src-homology region 2 (SH2) domain, and known to function upstream from p21ras, might form specific complexes with p210bcr-abl and thus, possibly alter p21ras activity by coupling to the guanine nucleotide exchange factor (Sos/CDC25) through the Grb2 protein-Sos complex. This latter complex has been previously demonstrated to occur ubiquitously. We found that p210bcr-abl formed a specific complex with Shc and with Grb2 in three different murine cell lines transfected with a p210bcr-abl expression vector. There appeared to be a higher order complex containing Shc, Grb2, and bcr-abl proteins. In contrast to p210bcr-abl transformed cells, in which there was constitutive tight association between Grb2 and Shc, binding between Grb2 and Shc was Steel factor (SLF)-dependent in a SLF-responsive, nontransformed parental cell line. The SLF-dependent association between Grb2 and Shc in nontransformed cells involved formation of a complex of Grb2 with c-kit receptor after SLF treatment. Thus, p210bcr-abl appears to function in a hematopoietic p21ras activation pathway to allow growth factor-independent coupling between Grb2, which exists in a complex with the guanine nucleotide exchange factor (Sos), and p21ras. Shc may not be required for Grb2-c-kit interaction, because it fails to bind strongly to c-kit.
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PMID:Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway. 750 97

ESKOL, a B-lymphoblastoid cell line consisting of late differentiated cells, resembles hairy cell leukemia (HCL). It is pseudodiploid with a deleted 7q and an unbalanced translocation between chromosomes 4 and 6. It was screened by Northern hybridization for oncogenes, including H-ras, c-raf-2 (c-raf1p1), c-kit, c-myc, c-myb, c-fos, Fim-1, c-jun, ski, and c-mos, which are believed to contribute to B-cell differentiation and maturation. Interferon-alpha-2b (IFN) downregulates the expression of H-ras, c-raf-2, c-kit, c-myc, c-myb, c-fos, as determined by Northern hybridization of RNA isolated from cells harvested at time points during a 30 h time course. Downregulation of oncogenes H-ras, c-raf-2, c-kit, whose proteins are associated with cell surfaces or are cytosolar transducers, occurs before those oncogenes c-myc, c-myb, and c-fos, whose products are DNA binding proteins. This suggests a temporal perturbation of signal transduction by IFN. No change in oncogene expression occurred in non-treated cells nor were these oncogenes expressed in the non-transformed B-lymphoblast cell line, Wil-2, under the same treatment regimen. The basis for the IFN perturbation is not understood; yet the role of these oncogenes as signal transducers in differentiation and proliferation of human hematopoietic progenitors is unfolding, and ESKOL is an excellent system in which to study this phenomenon.
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PMID:Interferon-alpha-2b downregulation of oncogenes H-ras, c-raf-2, c-kit, c-myc, c-myb and c-fos in ESKOL, a hairy cell leukemic line, results in temporal perturbation of signal transduction cascade. 752 May 17

The pleiotropic effects of the Kit receptor system are mediated by Kit-Ligand (KL) induced receptor autophosphorylation and its association with and activation of distinct second messengers, including phosphatidylinositol 3'-kinase (PI3-kinase), p21ras and mitogen-activated protein kinase (MAPK). To define the role of PI3-kinase, p21ras and MAPK in Kit-mediated cell proliferation, survival and adhesion in bone marrow-derived mast cells (BMMC), mutant Kit receptors were expressed in Wsh/Wsh BMMC lacking endogenous c-kit expression. The introduction of both murine Kit(S) and KitL (isoform containing a four amino acid insert) into Wsh/Wsh BMMC restored KL-induced proliferation, survival and adhesion to fibronectin, as well as activation of PI3-kinase, p21ras and MAPK, and induced expression of c-fos, junB, c-myc and c-myb mRNA. Substitution of tyrosine 719 in the kinase insert with phenylalanine (Y719F) abolished PI3-kinase activation, diminished c-fos and junB induction, and impaired KL-induced adhesion of BMMC to fibronectin. In addition, the Y719F mutation had partial effects on p21ras activation, cell proliferation and survival, while MAP kinase activation was not affected. On the other hand, Y821F substitution impaired proliferation and survival without affecting PI3-kinase, p21ras and MAPK activation, and induction of c-myc, c-myb, c-fos and c-jun mRNA, while KL-induced cell adhesion to fibronectin remained intact. In agreement with a role for PI3-kinase in Kit-mediated cell adhesion, wortmannin blocked Kit-mediated cell adhesion at concentrations known to specifically inhibit PI3-kinase. We conclude, that association of Kit with p85PI3-K, and thus with PI3-kinase activity, is necessary for a full mitogenic as well as adhesive response in mast cells. In contrast, tyrosine 821 is essential for Kit-mediated mitogenesis and survival, but not cell adhesion.
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PMID:Differential roles of PI3-kinase and Kit tyrosine 821 in Kit receptor-mediated proliferation, survival and cell adhesion in mast cells. 753 31

This study characterizes 3 cases of mesenchymal chondrosarcoma (MC) utilizing a proteomic approach that allows for the detection, visual quantification, cellular compartmentalization, and assessment of the functional state of certain proteins that may promote tumor growth and/or oppose apoptosis. Immunohistochemical procedures were performed to detect the following protein antigens: CD99, interleukin (IL)-1alpha, IL-6, transforming growth factor (TGF)-alpha, conventional (c) protein kinase C (cPKC)-alpha, cPKC-betaII, phosphorylated (p)-PKC-alpha/betaII, c-kit (CD117), platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)-2/neu, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, p21ras, the alpha subunit of farnesyl and geranylgeranyl transferase (FTalpha/GGTalpha), phospho (p)-c-Jun N-terminal kinase (p-JNK), p-p38 mitogen-activated protein kinase (MAPK), cyclin D1, c-Jun, Ki-67, bcl-2, TGF-beta1 latency-associated peptide (LAP), TGF-betaRII, and cyclooxygenase (COX)-2. Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. The results showed that malignant mesenchymal chondroblasts exhibit stronger expressions of CD99, IL-1alpha, cPKC-alpha, p-PKC-alpha/betaII, PDGFR-alpha, p-JNK, Ki-67, and bcl-2 antigens than their more mature-appearing chondrocytic counterparts in MC. In conclusion, molecular profiling of mesenchymal chondrosarcoma using a proteomic approach characterized the mesenchymal chondroblasts as possessing pathways that incorporate PKC-alpha and PDGFR-alpha signaling and anti-apoptotic bcl-2 expression. Specific therapies to target the mesenchymal chondroblasts in mesenchymal chondrosarcoma might include interferon-alpha, rapamycin, ciprofloxacin, and STI571.
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PMID:Mesenchymal chondrosarcoma: molecular characterization by a proteomic approach, with morphogenic and therapeutic implications. 1281 16

According to a two hit model of leukaemogenesis, the association between acute myeloid leukaemia (AML)1 mutations and FLT3 gene alterations has been recently described in M0 AML. To further document this model in M0 AML, we screened a cohort of 45 patients to find an association between genes implicated in myeloid differentiation (AML1, Pu1) and genes contributing to cell proliferation: (FLT3, N-RAS, K-RAS, c-KIT, PTPN11). No mutation of the Pu1 gene was observed, whereas mutation in the Runt domain of AML1 gene was observed in 12 of 45 patients (27%). No point mutation or insertion-deletion in the c-kit gene was found. Three point mutations (7%) and 11 internal tandem duplications (22%) were seen in FLT3 gene. Two N-Ras and one PTPN11 mutations were found. No significant correlation between AML1 mutation and FLT3 alteration was found. On the other hand, abnormal cytogenetic findings, especially unfavourable ones, were significantly more frequent in patients without detectable molecular abnormality. These findings suggest at least two different pathogenetic pathways in M0 AML: one associated with AML1 mutation, sometimes in combination with the activating lesion of the tyrosine kinase pathway and generally with normal karyotype, and the other with unfavourable cytogenetic findings.
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PMID:Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients. 1642 69

We previously showed that rasH2 transgenic mice carrying the human c-Ha-ras protooncogene are highly susceptible to chemical skin carcinogenesis. In the dermis of rasH2 mice, mast cells are recruited constitutively, and the number of mast cells increases more than in wild-type mice in response to treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. To determine whether enhanced skin tumor development in rasH2 mice is dependent on the recruitment of mast cells, we generated rasH2 KIT(W/Wv) mice by crossing rasH2 mice and W or W(v) KIT mutants, and examined the chemical skin carcinogenesis. In rasH2 KIT(W/Wv) mice, mast cells were not found in the dermis either before or after treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Papilloma multiplicity was up to 4.6-fold higher in rasH2 KIT(+/+) mice compared with their rasH2 KIT(W/Wv) siblings. At 12 weeks after the experiment began, the volumes of tumors were significantly smaller in rasH2 KIT(W/Wv) relative to rasH2 KIT(+/+) mice (rasH2 KIT(W/Wv): 29.2 +/- 19.9 mm(3) versus rasH2 KIT(+/+): 179.6 +/- 726.6 mm(3); P = 0.0153). There was no difference in the latency or multiplicity of papillomas between mice without the rasH2 transgene, KIT(W/Wv) mice and their wild-type littermates. Western blot analysis showed that expression of H-RAS protein in the skin was equivalent in rasH2 KIT(W/Wv) and rasH2 KIT(+/+) mice. In conclusion, the inhibition of c-kit decreased H-ras-induced skin carcinogenesis. The suppression of c-kit may be a unique and effective target as a preclinical model of cancer treatment where the activation of H-ras has a significant role. Targeting mast cells could also be a potential strategy for treating malignancies.
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PMID:Decreased c-kit function inhibits enhanced skin carcinogenesis in c-Ha-ras protooncogene transgenic mice. 1768 12

Neuroblastoma (NB) is the most common malignant solid tumor in childhood. There are well-recognized prognostic factors in NB such as age at diagnosis, organ of origin, stages, MYCN gene amplification, and expression of H-ras, trkA and survivin. Moreover, we investigated the expression of vascular endothelial growth factor (VEGF), tyrosine hydroxylase (TH), p53, stem cell factor (SCF) and c-kit of its receptor with quantitative real-time polymerase chain reaction (PCR) in 22 NBs and 4 other tumors (one malignant lymphoma, one malignant teratoma, and 2 rhabdomyosarcomas) samples. The correlation between patients' prognoses and the expression of TH or c-kit was newly recognized, particularly the good prognosis in patients in whom c-kit highly expressed and the poor prognosis contrarily associated with low or no expression, although the SCF of its ligand had no relationship with patient prognosis. It is possible that tumors without c-kit expression can not react with SCF (via the autocrine or paracrine system) and remain immature. It may be that this is a new critical clinical event in NB patients.
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PMID:Analyses of novel prognostic factors in neuroblastoma patients. 1805 15

Although the exact molecular mechanisms of Merkel cell carcinoma (MCC) tumorigenesis are unknown, they likely involve complex genetic alterations and mutations similar to those seen in many other cancers. In this study, we obtained MCCs from 21 elderly patients (19 women, 2 men) and analyzed their DNA for mutation of exons of interest in several tumor-suppressor genes or oncogenes known to be frequently mutated in skin cancer: p53 (exons 4-8), Ras (exons 1 and 2), c-Kit (exon 11), and the INK4a-ARF locus (encoding p14 and p16) (exons 1 and 2). Direct sequence analysis revealed p53 mutations (that is, at codons 224, 234, and 294) in three tumors (14%) and p16INK4a mutations (that is, at codon 6) in one (5%). No mutations were detected in Ha-Ras, Ki-Ras, N-Ras, c-Kit, or p14ARF. On the other hand, methylation-specific PCR revealed methylation of p14ARF promoter DNA in eight of 19 analyzable tumor samples (42%) and p16INK4a promoter DNA in one of 19 analyzable tumor samples (5%). Together, these findings suggest that p14ARF silencing may be an important mechanism in MCC tumorigenesis, and thus a potential target for therapeutic intervention in this highly aggressive tumor type.
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PMID:p14ARF hypermethylation is common but INK4a-ARF locus or p53 mutations are rare in Merkel cell carcinoma. 1821 79

Head and neck cancers (HNC) are 6th most common malignancies according to the incidence rate. Over 85% of tumors of this region are epithelial tumors, especially squamous cell carcinomas (head and neck squamous cell carcinomas - HNSCC). Surgery, chemotherapy and radiotherapy are still the standard for the treatment of HNC. Despite the great development of the various methods of treatment, survival of patients have not improved significantly over the last 30 years, with the overall, 5-year survival not exceeding 50%. Progress in understanding the biology of cancer leads to personalization of therapy and introduction of drugs with molecular mechanism of action to everyday practice. At present, the effectiveness of monoclonal antibodies against EGFR in the treatment of HNSCC has already been proven. Cetuximab in combination with radiotherapy was found to be effective in patients with advanced and locally advanced HNSCC. There are also some promising results of phase III trials with zalutumumab and panitumumab. Initial efficacy of sorafenib (an inhibitor of the intracellular domain of VEGFR, PDGFR and c-Kit) and afatinib (an irreversible inhibitor of pan-HER tyrosine kinase) have been demonstrated. Great hopes for the future are linked with the potential use of STAT3, EGFRvIII, abnormal proteins K-ras, H-ras and PTEN as well as proteasome as a target for therapy.
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PMID:Molecularly targeted therapies in head and neck cancers. 2303 18


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