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)

As an initial step to understand rapid growth of small cell lung cancer (SCLC), a complementary DNA library prepared from a SCLC cell line was screened with viral oncogene probes encoding protein-tyrosine kinases, which are known to play an important role in regulation of cell growth. Fifteen clones hybridizing with v-fms probe were isolated, and, by partial sequence analysis, four of them were identified to be c-kit protooncogenes. Northern blot study demonstrated that most of the SCLC tumors and cell lines expressed c-kit transcripts, while non-SCLC tumors and cell lines did not. Neither amplification nor rearrangement of the c-kit gene was demonstrated in SCLC cell lines by Southern blot analysis, however. Our results suggested that c-kit expression in SCLC reflects the unique biological nature of the tumor cells different from non-SCLC and further suggested that the c-kit product may participate in autocrine or paracrine stimulation of SCLC growth.
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PMID:Preferential expression of c-kit protooncogene transcripts in small cell lung cancer. 170 53

Recombinant human stem cell factor (SCF) binds to the c-kit receptor on human bone marrow progenitor cells and enhances their survival following irradiation. Since the c-kit receptor has also been detected on malignant cells, experiments were performed to study the effect of SCF on the proliferation and radiation survival of a variety of both c-kit-positive and -negative human tumor cell lines using [3H]thymidine incorporation and colony formation assays. The addition of SCF to both c-kit-positive and -negative cell line cultures had no significant effect on the stimulation index (in [3H]thymidine assay). In contrast, colony formation by H69 (small cell lung cancer cell line), H128 (small cell lung cancer cell line), and HEL (erythroid leukemia cell line) cells was enhanced by SCF in a dose-dependent manner, but SCF did not promote the in vivo growth of H128 xenograft tumors in terms of graft rate, time from implantation to tumor detection, or tumor size. Furthermore, SCF did not significantly increase the surviving fraction of either c-kit-positive or -negative cell lines following radiation, and there were no statistically significant differences between D0 [defined by the slope of the terminal exponential region of the two-component (single-hit multitarget model) survival curve where slope = 1/D0], Dq (quasithreshold dose), n (extrapolation number), alpha, and beta values for any of the cell lines studied that were irradiated with and without SCF. Finally, nude mice with transplanted human LG425 cutaneous T-cell lymphoma (c-kit positive) were treated with 10 Gy with or without SCF (100 micrograms/kg i.p. 20 h before, 2 h before, and 4 h after irradiation). There were no significant differences in the median tumor quadrupling time between groups that received either no treatment or SCF alone, or between groups treated with 10 Gy and SCF or 10 Gy alone (P > 0.05). These results are encouraging and suggest that SCF does not stimulate tumor cell proliferation in vivo or enhance the survival of tumor cells following irradiation.
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PMID:Effects of stem cell factor on the growth and radiation survival of tumor cells. 754 70

The proto-oncogene c-kit encodes a transmembrane tyrosine kinase receptor that is thought to play an important role in hematopoiesis, spermatogenesis, and melanogenesis. We previously showed that the c-kit messenger RNA is preferentially expressed in small cell lung cancer and that its ligand, stem cell factor, is expressed in a broad spectrum of human cancers. Using anti-c-kit antisera raised against synthetic peptides, in situ localization of the c-kit protein in various human solid tumors as well as in corresponding fetal and adult normal tissues was studied by the ABC method. The results suggest that the c-kit gene products may be involved in the pathogenesis of a very restricted subset of human solid tumors such as small cell lung cancer. Interestingly, nuclear protein immunologically related to c-kit was found in both normal and neoplastic medullary cells of the adrenal gland.
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PMID:Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. 767 21

We examined a panel of 25 small cell lung cancer (SCLC) cell lines and nude mouse xenografts for expression of the proto-oncogenes c-met and c-kit, and for expression of the corresponding ligands, hepatocyte growth factor (HGF) (also known as scatter factor (SF)), and stem cell factor (SCF), respectively. Expression of mRNA was detected by Northern blotting, and c-met and c-kit protein expression was detected by Western blotting and immunocytochemistry. c-met and c-kit mRNA was expressed in 22 of the examined cell lines or xenografts, and coexpression of the two proto-oncogenes was observed in 20 tumours. Expression of c-met and c-kit protein paralleled in the mRNA expression. HGF/SF mRNA was expressed in two of the examined tumours, and only one of these also expressed the c-met proto-oncogene. SCF mRNA was expressed in 19 of the examined tumours, and in 18 of these coexpression of c-kit and SCF was present. The high percentage of SCLC tumours expressing c-met and c-kit indicates that these proto-oncogenes may have an important function in this disease. The rare coexpression of c-met and HGF/SF is evidence that an autocrine regulatory pathway is not present for this receptor/ligand system in SCLC, while the frequent coexpression of c-kit and SCF indicates that this receptor/ligand system may have an autocrine function in SCLC.
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PMID:Expression of the proto-oncogenes c-met and c-kit and their ligands, hepatocyte growth factor/scatter factor and stem cell factor, in SCLC cell lines and xenografts. 767 80

The mRNAs encoding the c-kit protooncogene tyrosine kinase receptor and its ligand, hemopoietic stem cell factor, are coexpressed in the majority of small cell lung cancer cell lines, suggesting that an autocrine growth loop may exist. Functional c-kit protein levels correspond well with mRNA levels in these cells. We have observed that those cell lines which express the c-kit gene also express either the L- and N-myc genes; those cell lines which express the c-myc gene do not express the c-kit gene. We have determined, by analyzing several small lung cancer cell lines transfected with a c-myc expression vector, that heterologous expression of c-myc correlates with a marked down-regulation of c-kit expression. Regulation of c-kit expression by the myc gene family may be partly responsible for the differing biological properties of cell lines and tumors which express N- and L-myc versus those that express c-myc.
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PMID:c-myc expression correlates with suppression of c-kit protooncogene expression in small cell lung cancer cell lines. 768 33

Lung cancer is the leading cause of cancer death in the United States. Small cell lung cancer (SCLC) accounts for 20% to 25% of all bronchogenic carcinoma and is associated with the poorest 5-year survival of all histologic types. SCLC differs in its etiologic, pathologic, biologic, and clinical features from non-SCLC, and these differences have translated to distinct approaches to its prevention and treatment. Compared with other histologic types of lung cancer, exposures to tobacco smoke, ionizing radiation, and chloromethyl ethers pose a substantially greater risk for development of SCLC. The histologic classification of SCLC has been revised to include three categories: (1) small cell carcinoma, (2) mixed small cell/large cell, and (3) combined small cell carcinoma. Ultrastructurally, SCLC displays a number of neuroendocrine features in common with pulmonary neuroendocrine cells, including dense core vesicles or neurosecretory granules. These dense core vesicles are associated with a variety of secretory products, cell surface antigens, and enzymes. The biology of SCLC is complex. The activation of a number of dominant proto-oncogenes and the inactivation of tumor suppressor genes in SCLC have been described. Dominant proto-oncogenes that have been found to be amplified or overexpressed in SCLC include the myc family, c-myb, c-kit, c-jun, and c-src. Altered expression of two tumor suppressor genes in SCLC, p53 and the retinoblastoma gene product, has been demonstrated. Cytogenetic and molecular evidence for chromosomal loss of 3p, 5q, 9p, 11p, 13q, and 17p in SCLC has intensified the search for other tumor suppressor genes with potential import in this malignancy. Bombesin/gastrin-releasing peptide, insulin-like growth factor I, and transferrin have been identified as autocrine growth factors in SCLC, with a number of other peptides under active investigation. Several mechanisms of drug resistance in SCLC have been described, including gene amplification, the recently described overexpression of multi-drug resistance-related protein (MRP), and the expression of P-glycoprotein. The classic SCLC staging system has been supplanted by a revised TNM staging system where limited disease and extensive disease are equivalent to the TNM stages I through III and stage IV, respectively. Therapeutically, recent strategies have attained small improvements in survival but significant reductions in the toxicities of chemotherapeutic regimens. Presently, the overall 5-year survival for SCLC is 5% to 10%, with limited disease associated with a significantly higher survival rate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Small cell lung cancer: etiology, biology, clinical features, staging, and treatment. 839 98

At least 70% of small cell lung cancer (SCLC) tumors and tumor-derived cell lines coexpress the genes for stem cell factor (SCF) and its receptor, the c-kit proto-oncogene. To assess the impact of coexpression of the growth factor and receptor on SCLC growth, the NCI-H146 SCLC cell line, which expresses only SCF, was transfected with a c-kit expression vector. Kit protein immunoprecipitated from the transfected cells had a constitutive level of tyrosine phosphorylation, and these cells grew more vigorously in serum-free medium compared to control-transfected cells. This growth advantage could be blocked by the addition of the tyrosine kinase inhibitor herbimycin A. Growth of the c-kit-transfected cells could be further enhanced by the addition of bombesin or insulin-like growth factor-1, suggesting that the SCF/c-kit autocrine loop could function cooperatively with other SCLC autocrine loops. To further investigate the importance of this autocrine loop, a cell line that naturally coexpresses SCF and c-kit was transfected with a kinase-defective c-kit gene. Cells transfected with the defective gene showed a marked decrease in their ability to grow under growth factor-free conditions compared to cells transfected with the empty expression vector. Taken together, these studies demonstrate that the coexpression of the stem cell factor and c-kit genes is a major contributor to the growth factor independence of SCLC.
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PMID:Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. 854 94

Thrombopoietin (TPO) is a recently discovered hematopoietic growth factor which stimulates the production and maturation of megakaryocytes. In this study, we used a modified MTT assay to examine the in vitro growth-stimulatory effects of recombinant human (rh) TPO and recombinant human stem cell factor (rhSCF) on eight small cell lung cancer (SCLC) cell lines and one leukemic cell line, CMK, with megakaryocytic characteristics. rhTPO did not reveal any stimulatory effects on all eight SCLC cell lines, while rhSCF demonstrated a modest growth-stimulatory effect on one etoposide-resistant SCLC cell line (H69/VP). The transcripts of c-mpl, the receptor of TPO, was not detected in all SCLC cell lines by RT-PCR analysis, while those of c-kit, the receptor of SCF, were detected in five of eight SCLC cell lines. Our data suggest that rhTPO does not promote the growth of SCLC cell lines and may be clinically applicable for patients with this disease. Moreover, rhSCF may cause adverse effects in part of the SCLC patients.
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PMID:Lack of c-mpl proto-oncogene transcripts and growth-stimulatory effects of thrombopoietin on human small cell lung cancer cell lines. 878 80

Recent results from molecular biology have shown that lung cancer is characterized by multiple, sequentially appearing molecular changes that include genetic and epigenetic alterations. Among all types of lung cancer, small cell lung cancer (SCLC) is associated with the lowest rate of 5-year survival. In this symposium, we introduce our findings regarding the c-kit oncogenes in SCLC. We found that the c-kit gene is strongly expressed in SCLC. The c-kit gene was not expressed in normal bronchial epithelial cells, which indicates that this gene is abberantly transcribed in SCLC. In addition, c-kit-positive cases of SCLC showed autophosphorylation in response to recombinant human stem cell factor. Furthermore, adding rh stem cell factor of SCLC cell lines induced a significant chemotactic response and moderate in vitro cell growth. These results strongly suggest that abnormal expression of the c-kit gene may be involved in the pathogenesis of SCLC by autocrine/paracrine stimulation via the c-kit/SCF signal pathway. To overcome drug resistance, we assessed the efficacy of a chimeric toxin targeted to c-kit receptors.
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PMID:[A new strategy for treating small cell lung cancer]. 921 97

Small cell lung cancer (SCLC) is an aggressive cancer characterized by several autocrine growth mechanisms including stem cell factor and its receptor c-Kit. In order to arrive at potentially new and novel therapy for SCLC, we have investigated the effects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines. It has been previously reported that STI 571 does not only inhibit cellular Abl tyrosine kinase activity but also the PDGF receptor and c-Kit tyrosine kinases at similar concentrations (approximately 0.1 microM). There is no expression of the PDGF-receptor, and the Abl kinase is not activated by SCLC, but over 70% of SCLC contain the c-Kit receptor. Utilizing this preliminary data, we have determined that three (NCI-H69, NCI-H146 and NCI-H209) of five (including NCI-H82 and NCI-H249) SCLC cell lines had detectable c-Kit receptors and were inhibited in growth and viability at concentrations 1 - 5 microM of STI 571 after 48 h of treatment. The SCLC cell lines, NCI-H69, NCI-H146 and NCI-H209, showed a dose-response (tested between 0.1 - 10 microM) inhibition of tyrosine phosphorylation of c-Kit as well as in vitro kinase activity (at 5 microM) of c-Kit in response to STI 571. STI 571 inhibited cell motility, as assessed by time-lapsed video microscopy, within 6 h of STI 571 treatment (5 microM). STI 571 also decreased intracellular levels of reactive oxygen species (ROS) by at least 60%, at a concentration (5 microM) that also inhibited cell growth. Cell cycle analysis of STI 571 responsive cells showed that cells were generally slowed in G2/M phase, but there was no arrest at G1/S. A downstream phosphorylation target of c-Kit, Akt, was not phosphorylated in response to stem cell factor in the presence of STI 571. These data imply that STI 571 inhibits growth of SCLC cells through a mechanism that involves inactivation of the tyrosine kinase c-Kit. The effectiveness of STI 571 in this study suggests this drug may be useful in a clinical trial, for patients with SCLC. Oncogene (2000) 19, 3521 - 3528
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PMID:Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. 1091 10


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