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)

A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.
Cancer Res 1994 Dec 01
PMID:Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. 795 56

We have utilized highly purified hematopoietic progenitor and stem cells (HPCs, HSCs) from normal peripheral blood to develop methodology for: (a) efficient transfer into HPCs of a non-hematopoietic membrane reporter, i.e., the nerve growth factor receptor complementary DNA; and (b) effective gene transduction of putative HSCs, i.e., cells initiating Dexter-type long-term culture (LTC-ICs). Purified HPCs induced into cycling by growth factors (interleukin 3, interleukin 6, c-kit ligand) were transduced with the N2 retroviral vector containing the neomycin resistance (neor) gene. More than 80% of transduced HPCs were resistant to the toxic G418 level. Thereafter, the HPCs were effectively transduced with the LNSN retroviral vector containing a nerve growth factor receptor complementary DNA; the nerve growth factor receptor was detected on > or = 18% of the transduced HPCs. These experiments provide a new tool from which (a) to monitor expression of a transduced membrane report on hematopoietic cells, particularly at the level of HPCs/HSCs, and (b) to characterize the transduced cells by double- and triple-labeling membrane antigen analysis. Purified HPCs/HSCs grown in Dexter-type LTC were transduced at 1 week by exposure to supernatant N2 retroviral particles in the absence of exogenous hematopoietic growth factors. The procedure, devoid of toxic effects, allowed an efficient neor transduction into LTC-ICs. Thus, we consistently detected neomycin-resistant mRNA in the clonal progeny of HPCs produced in LTC at 5-8 weeks in both the nonadherent and adherent fractions; this timing of expression coincides with that of HPC production by LTC-ICs, thereby indicating the effective transduction of the LTC-ICs. These experiments represent a first step toward development of preclinical models for gene transfer into human peripheral blood HSCs by complex retroviral vectors.
Cancer Res 1994 Aug 15
PMID:Efficient transfer of selectable and membrane reporter genes in hematopoietic progenitor and stem cells purified from human peripheral blood. 804 88

The tumor suppressor gene p53 is the most frequently mutated gene in human cancer. We have used polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing to examine the status of the p53 gene in human testicular cancers of various histologies. We were unable to find in 40 samples and four cell lines any mutations in the regions of this gene (exons 5 through 8) that are usually mutated in other cancers. Northern blot analysis showed expression of this gene in most of the samples analyzed, as well as in four human testicular tumor cell lines. The MDM-2 gene is amplified and overexpressed in sarcomas; it binds and functionally inactivates p53. The 44 testicular tumor samples and cell lines were examined for amplification of MDM-2 by dot-blot analysis; none was found. The proto-oncogene c-kit probably plays an important role in normal testicular development. Mutation of the tyrosine phosphorylation site of a closely related member of this family of tyrosine kinase receptors (c-fms) is associated with cellular transformation and cancer. Codon 936 is the analogous tyrosine of c-kit; using polymerase chain reaction-single-strand conformation polymorphism analyses, we were unable to detect mutations at this site in our 44 testicular cancer samples. We conclude from our studies that mutations in the most conserved region of the p53 gene, as well as at codon 936 of the c-kit gene and amplification of MDM-2, are extremely rare in human testicular cancers.
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PMID:Mutations of the p53 gene are not detectable in human testicular tumors. 806 72

SL/Kh mice spontaneously develop pre-B lymphomas with surface phenotypes of B220+, BP-1+, Thy-1-, and surface immunoglobulin negative. The immunoglobulin heavy chain of lymphoma is clonally rearranged but the light chain gene remains in germline configuration. Studying prelymphoma stage SL/Kh bone marrow (BM), we found unusual multiclonal expansion of BP-1+ pre-B cells [34.8 +/- 5.8% (mean +/- SD)] by 4 weeks of age, whereas there were far fewer of such cells in most other laboratory strains (8 +/- 5%). The BP-1+ cells did not express surface immunoglobulin, Thy-1.1, or c-kit. Therefore, they seemed to belong to the pre-B II category. Increased numbers of BP-1+ cells were seen in F1 hybrids between SL/Kh and NFS/N; thus it was apparently a dominant heritable property of SL/Kh mice. Emergence of this population was independent of expression of endogenous ecotropic virus, since they were present in BMs of the F1 hybrid to C4W (Fv-4') and were not inhibited by neonatal injection of maternal resistance factor. In the radiation chimeras SL/Kh-->BALB/c, BP-1+ cells appeared abundantly (29.0 +/- 3.8%), whereas in the reciprocal chimeras BALB/c-->SL/Kh, for fewer (5.5 +/- 2.3%) appeared. Therefore, expansion of BP-1+ cells in prelymphomatous BM is a property of SL/Kh stem cells rather than BM microenvironments.
Cancer Res 1994 Jan 15
PMID:Abnormal bone marrow B-cell differentiation in pre-B lymphoma-prone SL/Kh mice. 827 75

Similar to two other hematopoietic growth factor receptors, the c-fms (macrophage colony-stimulating factor receptor) and the c-kit genes, c-mpl has been discovered through the study of oncogenic retroviruses. Unlike c-fms and c-kit, which both belong to a subgroup of tyrosine kinase receptors, the c-mpl proto-oncogene encodes a new member of the cytokine receptor superfamily. We have studied the expression of c-mpl in a series of 105 patients with hematologic malignancies using Northern blot analysis. The levels of c-mpl transcripts in lymphoid malignancies and in chronic myeloproliferative disorders were not significantly different from those found in normal bone marrow cells, in which c-mpl was barely detectable. In contrast, c-mpl expression was increased in 26 of 51 patients with acute myeloblastic leukemia (AML) and in 5 of 16 patients with myelodysplastic syndromes. Amplification of the c-mpl gene was detected in genomic DNA of one M4 AML patient. There was no significant correlation between c-mpl expression and the French-American-British classification of AML. Patients with high c-mpl expression appeared to belong to a subgroup of AML with a low rate of complete remission and a poor prognosis, including secondary leukemia and AML with unfavorable cytogenetic abnormalities.
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PMID:Expression of the c-mpl proto-oncogene in human hematologic malignancies. 839 55

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)
Curr Probl Cancer
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.
Cancer Res 1996 Jan 15
PMID:Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. 854 94

We report that blood cell autografts, collected by single leukapheresis in cancer patients (n = 11) at the time of mobilization of hematopoietic progenitors into peripheral blood following anticancer therapy with high-dose cyclophosphamide (HD-CTX) plus interleukin-3 (IL-3) and granulocyte colony-stimulating factor (G-CSF/filgrastim), comprise 1.98 +/- 0.39 x 10(5)/kg (mean +/- SE) CD34+ progenitors of dendritic cells (DCs). This number corresponds to 140-fold more progenitors than in a control autograft collected in the steady state. DCs derived from mobilized CD34+ cells, morphologically and immunophenotypically undistinguishable from skin Langerhans cells and DCs from bone marrow and cord blood CD34+ cells, are shown to be powerful stimulators of allogeneic T cell proliferation in primary MLR and of autologous HLA-DR-restricted CD4+ T cell proliferation in response to presentation of xenogenic antigens. We show that the GM-CSF-plus-TNF-alpha-dependent ex vivo generation of DCs from mobilized CD34+ cells is 2.5-fold enhanced by flk-2/flt-3 ligand or c-kit ligand (stem cell factor) and five-fold enhanced by a combination of these growth factors. In addition, the optimal serum for the generation of DCs is autologous HD-CTX recovery-phase serum rather than fetal calf serum (FCS) or steady-state human serum, which are clinically inadequate and ineffective, respectively. In practice, the stimulation of CD34+ cells in a blood cell autograft (15.75 +/- 2.46 x 10(6)/kg) provided by the above four growth factors should permit ex vivo generation of approximately 40 x 10(9) DCs in an adult patient. These new findings provide advantageous tools for the large-scale generation of DCs that are potentially usable for clinical protocols of immunotherapy or vaccination in patients undergoing cancer treatment.
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PMID:Massive ex vivo generation of functional dendritic cells from mobilized CD34+ blood progenitors for anticancer therapy. 854 32

The proto-oncogene c-kit and its ligand stem-cell factor (SCF) may play an important role in the development of normal and malignant testicular tissue. This study investigates the presence of SCF and c-kit protein in 32 orchiectomy specimens of patients with testicular cancer, in 5 specimens of normal testicular tissue and in three established non-seminomatous germ-cell cancer cell lines (H12.1, H32, 577ML) by an immunohistochemical approach. Out of 9 testicular cancer specimens classified as pure seminomas, 7 (78%) showed a strong immunohistochemical reaction for both SCF and c-kit protein on the surface of the tumour cells. Fourteen non-seminomatous germ-cell tumours composed of embryonal carcinoma were completely negative for both SCF and c-kit proteins and only faint positivity was found in 6 tumours (26%). Differentiated teratomatous structures within the specimens on non-seminomatous tumours showed a strong immunohistochemical reaction for SCF and c-kit protein in 8 of 11 (73%) cases. All three testicular cancer cell lines showed only faint staining reactions for c-kit protein and none for SCF. No secretion of SCF by the three lines in vitro was detected. The addition of high concentrations of SCF (100 ng/ml) to the testicular cancer cell lines in culture conditions without fetal calf serum resulted in a 1.4 to 3-fold growth stimulation compared to cell growth in serum-free medium alone. This effect was not detectable when the cells were cultured in serum-containing media. In the normal testicular tissue the germ-cells displayed a strong immunohistochemical reaction for c-kit protein while SCF positivity was found at the tubular membrane and on the surface of Sertoli cells. The SCF/c-kit system may possess a regulatory function in normal testicular tissue by possibly providing the microenvironment necessary for spermatogenesis. With the development of testicular cancer, this regulatory system seems to be lost, particularly in non-seminomatous germ-cell tumours. A growth-stimulatory effect of high concentrations of SCF on non-seminomatous testicular cancer cell lines can be detected only in culture conditions with serum-free media. The effects achievable by the combination of SCF with other growth factors need to be further studied, as well as the role of the c-kit/SCF regulatory system for normal spermatogenesis and its possible implications for the understanding and treatment of male infertility.
J Cancer Res Clin Oncol 1996
PMID:Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours. 860 54

A novel human leukemia cell line (Kasumi-3) was established from the blast cells of a 57-year-old man suffering from myeloperoxidase-negative acute leukemia. The cell line had five distinctive features, as follows. 1) Flow cytometric analyses showed cell surface expression of CD7, CD4, CD13, CD33, CD34, HLA-DR and c-Kit. This phenotype is compatible with that of acute myelocytic leukemia cells with the M0 subtype in the French-American-British classification. 2) Kasumi-3 cells carried chromosomal abnormalities of t(3;7)(q27:q22), del(5)(q15), del(9)(q32), and add(12)(p11). The breakpoint of 3q27 was located near the EVI1 gene, and a high level of expression of the EVI1 gene was observed. 4) Kasumi-3 cells treated with TPA showed maturation to monocytic lineage. 5) Treatment with either interleukin (IL)-2, IL-3, IL-4, granulocyte-macrophage colony-stimulating or stem cell factor induced the proliferation of Kasumi-3 cells. Thus, the Kasumi-3 cell line shows the characteristic features of undifferentiated leukemia. It should, therefore, be useful both for studying the biological characteristics of acute myelogenous leukemia M0 subtype and for investigating the role of the EVI1 gene in leukemogenesis.
Jpn J Cancer Res 1996 Mar
PMID:Establishment of an undifferentiated leukemia cell line (Kasumi-3) with t(3;7)(q27;q22) and activation of the EVI1 gene. 861 29


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