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 human stem cell factor (SCF), also termed c-Kit ligand (KL), is a hematopoietic growth factor produced by mesenchymal cells that induces proliferation of bone marrow progenitor cells, megakaryocytes, and mast cells via interaction with c-Kit, its cognate receptor. Expression of the c-kit gene was identified in human platelets by the polymerase chain reaction technique. The presence of the c-Kit receptor was demonstrated by the specific binding of 125I-KL/SCF to ADP-stimulated platelets. The identity of the c-Kit protein was confirmed by immunoreactivity with an anti-c-Kit-specific antibody and by its characterization as a phosphotyrosine-containing protein. Under constitutive conditions, c-Kit was found to be tyrosine-phosphorylated and was associated with a 85-kDa phosphoprotein that could be a fragment of phosphatidylinositol 3-kinase. These data indicate the presence of a new platelet surface molecule that could function in platelet activation. We demonstrate that the secondary wave of platelet aggregation and serotonin secretion induced by epinephrine and ADP, but not by the thromboxane analog U46619, was augmented by KL/SCF. The effect of KL/SCF on epinephrine/ADP-induced platelet activation appeared to be mediated in part through the thromboxane pathway. These data suggest that KL/SCF could modulate hemostasis via interaction with platelets, particularly in conditions where mesenchymal cells are exposed to circulating blood elements, such as in wound healing or atherosclerosis.
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PMID:Human kit ligand (stem cell factor) modulates platelet activation in vitro. 752 Apr 41

Recombinant thrombopoietin has been reported to stimulate megakaryocytopoiesis and thrombopoiesis and it may be quite useful to treat patients with low platelet counts after chemotherapy. As little is known regarding the possible activation of platelets by thrombopoietin, we examined the effects of thrombopoietin on platelet aggregation induced by shear stress and various agonists in native plasma. Using hirudin as an anticoagulant, thrombopoietin (1 to 100 ng/mL) enhanced platelet aggregation induced by 2 micromol/L adenosine-diphosphate (ADP) in a dose dependent fashion. The enhancement was not affected by treatment of platelets with 1 mmol/L aspirin plus SQ-29548 (a thromboxane antagonist, 1 micromol/L) but was inhibited by a soluble form of the thrombopoietin receptor, suggesting that the enhancement was mediated by the specific receptors and does not require thromboxane production. Epinephrine (1 micromol/L), which does not induce platelet aggregation in hirudin platelet rich plasma (PRP), did so in the presence of thrombopoietin (10 ng/mL). Thrombopoietin (10 ng/mL) also enhanced or primed platelet aggregation induced by collagen (0.5 micron.mL),. thrombin, serotonin, and vasopressin. Thrombopoietin does not induce any rise in cytosolic ionized calcium concentration nor activation of protein kinase C, as estimated by phosphorylation of preckstrin, indicating that the priming effects of thrombopoietin does not require those processes. The ADP- or thrombin-induced rise in cytosolic ionized calcium concentration was not enhanced by thrombopoietin (100 ng/mL). Further, shear (ca. 90 dyn/cm2)-induced platelet aggregation was also potentiated by thrombopoietin. The priming effect on epinephrine-induced platelet aggregation in hirudin PRP was unique to thrombopoietin, with no effects seen using interleukin-6 (IL-6), IL-11, IL-3, erythropoietin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, or c-kit ligand. These data indicate that monitoring of platelet functions may be necessary in the clinical trials of thrombopoietin.
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PMID:Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists. 863 35

Receptor tyrosine kinase (RTK) enzymes regulate cell signaling pathways and so are an important target for cancer chemotherapy. Current inhibitors of c-kit, a key RTK stem cell factor receptor, are inactive against the most common mutated variant Asp816Val, associated with highly malignant cancers. Recent combined experimental/simulation work has highlighted the utility of the ellipticine pharmacore in inhibiting mutant c-kit, and the present simulation study applies a combination of high-level simulation tools to probe further the binding of ellipticine-based derivatives to c-kit. We find a large preference for protonation of bound ellipticine, which stabilizes the negative protein residues that coordinated ADP.Mg (2+) in the native complex. The resulting ellipticine inhibitor binding mode resembles the native nucleotide complex and serves to explain some existing experimental data on binding specificities, indicating that functionalization at the C4/C5 sites of ellipticine derivatives may be important for the design of novel nucleotide analogues that inhibit mutant c-kit.
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PMID:Computer simulations reveal a novel nucleotide-type binding orientation for ellipticine-based anticancer c-kit kinase inhibitors. 1875 82

Hepatocellular carcinoma (HCC) is associated with a high morbidity and mortality due to its high rate of recurrence. However, little is known about the biological characteristics of recurrent HCC cells. A single patient's primary and recurrent HCC-derived cell lines, Hep-11 and Hep-12, respectively, were established by primary culture. These two cell lines have the same hepatitis B virus integration site and share many common amplifications and deletions, which suggest that they have the same clonal origin. While Hep-11 cells were non-tumorigenic at 16 weeks following injection of up to 10 000 cells, injection of only 100 Hep-12 cells was sufficient to initiate tumor growth, and all single Hep-12 clones were tumorigenic in immunodeficient mice. Compared with Hep-11, Hep-12 cells expressed the oval cell markers AFP, NCAM/CD56, c-kit/CD117, as well as multiple stem cell markers such as Nanog, OCT4 and SOX2. In addition, >90% of Hep-12 cells were aldehyde dehydrogenase positive. They were also less resistant to paclitaxel, but more resistant to doxorubicin, cisplatin and hydroxycamptothecin (HCPT), which had been administrated to the patient. Furthermore, Hep-12 cells expressed higher levels of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) than Hep-11, and PARP-1 inhibition potentiated the sensitivity to HCPT in Hep-12 cells but not in Hep-11 cells. These results indicate that a large population of the recurrent HCC-derived Hep-12 cells were tumor-initiating cells and that elevated expression of PARP-1 was related to their resistance to HCPT.
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PMID:The properties of tumor-initiating cells from a hepatocellular carcinoma patient's primary and recurrent tumor. 1989 2