Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concept of autocrine stimulation of cell proliferation postulates growth autonomy by acquisition of the ability to produce and respond to growth factors. Overproduction of several growth factors in a variety of human tumors and cell lines derived from these tumors has been reported. We have screened several cell lines derived from glioblastomas for anomalies in the expression of genes encoding transforming growth factor alpha (TGF-alpha), TGF-beta, basic fibroblast growth factor (bFGF) and its high-affinity receptor, flg. Compared with normal human brain tissue, we observed a generalized elevation in the levels of expression of these genes in glioblastoma cell lines and an SV40-transformed human astroglial cell line. Overexpression of these genes does not appear to be merely a reflection of the proliferative state of transformed cells since some other human tumor cell lines, when analysed for the expression of TGF-beta and bFGF, did not show a significant increase in these transcripts. The specificity of the elevated transcription of TGF-alpha, TGF-beta, bFGF and flg in glioblastoma cell lines is further suggested by the fact that the transcription of the proto-oncogene c-erbB2, which is overproduced in breast tumor cell lines, was not elevated in glioblastoma cell lines. Increased expression of growth factors, which are potent mitogens and angiogens, and/or their receptors may have critical roles in autonomous proliferation as well as neovascularization of glioblastomas.
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PMID:Increased expression of genes from growth factor signaling pathways in glioblastoma cell lines. 134 15

The c-kit proto-oncogene encodes a 145- to 160-Kd transmembrane tyrosine kinase, which is a member of the platelet-derived growth factor receptor family and is allelic with the murine white spotting locus (W). W mutations affect several aspects of hematopoiesis, most notably erythroid progenitors and mast cells. A monoclonal antibody, YB5.B8, had been raised against the leukemic blasts of a patient with M1-type acute myelocytic leukemia (AML) and it precipitates a 150-Kd cell surface glycoprotein from leukemic cells. The YB5.B8 epitope is expressed on mast cells, on up to 3% of normal mononuclear bone marrow cells, and it identifies a sub-group of AML patients with a poor prognosis. In view of similarities noted between the cell surface antigen identified by YB5.B8 and the c-kit protein product, we performed experiments to determine whether they are identical. c-kit RNA expression in the cell lines HEL (human erythroleukemia) and A172 (glioblastoma) was shown to parallel the expression of the YB5.B8 epitope in these lines as measured by flow cytometry. Immunoprecipitation analysis with anti-kit serum and YB5.B8 antibody indicated that the two antibodies identified proteins of identical size in HEL (155 Kd) and A172 (145 Kd) cells, and sequential immunoprecipitations with the kit and the YB5.B8 antibodies demonstrated that the two antibodies recognize the same molecule. The proteins identified by both the anti-kit and YB5.B8 antibodies displayed in vitro autophosphorylation activity in immune complex kinase assays. In addition, YB5.B8 was able to inhibit the binding of the kit ligand to HEL cells. These studies provide evidence that the YB5.B8 antigen and the c-kit protein product are identical and raise certain hypotheses regarding the role of c-kit in AML.
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PMID:Monoclonal antibody YB5.B8 identifies the human c-kit protein product. 170 91

Structural features of v-kit, the oncogene of HZ4 feline sarcoma virus, suggested that this gene arose by transduction and truncation of cellular sequences. Complementary DNA cloning of the human proto-oncogene coding for a receptor tyrosine kinase confirmed this possibility: c-kit encodes a transmembrane glycoprotein that is structurally related to the receptor for macrophage growth factor (CSF-1) and the receptor for platelet-derived growth factor. The c-kit gene is widely expressed as a single, 5-kb transcript, and it is localized to human chromosome 4 and to mouse chromosome 5. A c-kit peptide antibody permitted the identification of a 145,000 dalton c-kit gene product that is inserted in the cellular plasma membrane and is capable of self-phosphorylation on tyrosine residues in both human glioblastoma cells and transfected mouse fibroblasts. Our results suggest that p145c-kit functions as a cell surface receptor for an as yet unidentified ligand. Furthermore, carboxy- and amino-terminal truncations that occurred during the viral transduction process are likely to have generated the transformation potential of v-kit.
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PMID:Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. 244 37

Five human glioblastoma cell lines were analyzed for oncogene activation with a panel of probes. Abnormal expression of the epidermal growth factor receptor (EGFr) gene was detected in four of five lines; N-ras oncogene overexpression was found in all five cell lines. These results were subsequently confirmed with fresh brain tumor and nonneoplastic brain tissue biopsy samples; increased expression of the N-ras proto-oncogene was observed in five of five glioblastomas, all of which also showed EGFr gene overexpression, but not in well-differentiated gliomas or in nonneoplastic brain tissue specimens. No significant differences in Ha-ras and Ki-ras expression were observed. Preliminary histochemical observations showed that intracellular levels of transforming growth factor alpha, a putative biochemical link between these two oncogenes, were significantly higher in glioblastoma cells than in controls.
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PMID:Overexpression of N-ras oncogene and epidermal growth factor receptor gene in human glioblastomas. 290 20

B-cell stimulatory factor 2 (BSF-2) is a lymphokine which induces the final maturation of B cells. BSF-2 acts on a variety of cells other than B cells, and moreover, expression of BSF-2 mRNA is detected in interleukin-1 beta-stimulated glioblastoma and astrocytoma cell lines. Here, we studied the function of BSF-2 on pheochromocytoma PC12 cells, a model system for induction of neuronal differentiation. PC12 cells possess specific receptors for BSF-2. The BSF-2-stimulated PC12 cells expressed the c-fos proto-oncogene transiently, and they began to change morphologically to neurite-extending cells after several days. The number of voltage-dependent Na+ channels was also increased.
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PMID:Induction of neuronal differentiation in PC12 cells by B-cell stimulatory factor 2/interleukin 6. 326 80

The c-kit proto-oncogene encodes a tyrosine kinase receptor for stem cell factor and plays a critical role in the growth and differentiation of various types of cells including hematopoietic stem cells. To investigate the mechanisms of its transcriptional regulation, we isolated the 5' flanking region of the human c-kit gene and characterized its promoter activity in hematopoietic cells. Nucleotide sequence analysis revealed that the 1.2 kb 5' flanking region lacked a typical "TATA box," but had a relatively high G + C content and four potential Sp1-binding sites. Putative binding sites for AP-2, basic helix-loop-helix proteins, Ets-domain proteins, Myb and GATA-1 were also found. Primer extension and S1 nuclease protection analyses of hematopoietic cells indicated that the major transcription start sites are 62 bp and 58 bp upstream of the translation start site. Essentially the same start sites were detected in non-hematopoietic cells such as small cell lung carcinoma and glioblastoma: this single promoter in c-kit is different from the multiple promoter system of c-fms, a c-kit-related gene, in which at least two promoters are differently used in hematopoietic and non-hematopoietic cells. An analysis of the c-kit 5' flanking region using the bacterial chloramphenicol acetyltransferase gene (CAT assay) in human erythroleukemia HEL cells, which express the endogenous c-kit mRNA at high levels, showed that a region from -180 to -22 is important for the expression of the c-kit gene. In addition, a negative regulatory element(s) is suggested to be involved in the regulation of the c-kit gene expression in mammals.
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PMID:Characterization of the promoter region of the human c-kit proto-oncogene. 750 48

CD34 is currently the only well defined human hematopoietic stem cell marker and is expressed on 1-4% of normal bone marrow cells. Putative binding sites for Ets proteins, a family of transcription factors involved in the regulation of cell differentiation and proliferation in many cell systems, are present in the 5'-flanking region of the CD34 gene. Some of these sites are in close proximity to binding sequences of the encoded product of the proto-oncogene c-myb, which regulates CD34 expression by interacting with the Myb binding sites. Here we demonstrate that Ets-2 (i) transactivates the CD34 promoter in rodent fibroblasts upon interaction with Ets binding sites and (ii) induces expression of CD34 mRNA and protein in the CD34- human glioblastoma T98G cells. Ets-2 and c-Myb transactivate the CD34 promoter independently because specific transactivation is abrogated by site-specific mutations of the binding sites or by competition with oligomers that include wild type but not mutated Myb or Ets binding sites. Ets-2 and c-Myb appear to have addictive effects on transactivation of the CD34 promoter and on induction of CD34 mRNA. Instead, CD34 surface protein levels might be induced synergistically, raising the possibility of a posttranslational mechanism of CD34 expression in cells constitutively expressing c-Myb and Ets-2.
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PMID:Ets-2 and c-Myb act independently in regulating expression of the hematopoietic stem cell antigen CD34. 752 84

Colony stimulating factor 1 (CSF-1) is a functionally versatile, circulating homodimeric growth factor that stimulates the survival, proliferation, and differentiation of mononuclear phagocytic cells, the differentiation of osteoclast progenitor cells and that regulates cells of the female reproductive tract. CSF-1 is also expressed in the central nervous system where it may regulate the differentiation and activation of microglia. The diverse forms of CSF-1 are all encoded by a single gene. Alternative posttranscriptional splicing and posttranslational cleavage determines whether CSF-1 will be produced as a secreted proteoglycan, secreted glycoprotein, or as a cell-surface glycoprotein that may be involved in cell-cell interactions. CSF-1 is expressed in glioblastoma cell-lines, normal human astrocytes, and in operative specimens of human glioma. The CSF-1 receptor, encoded by the c-fms proto-oncogene, is also expressed in human gliomas. We conclude that coexpression of CSF-1 and its receptor in some human gliomas hints at a possible autocrine or paracrine growth stimulatory role for CSF-1; however, its function in the mammalian CNS remains to be elucidated.
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PMID:Colony stimulating factor-1 expression in human glioma. 808 34

We have previously reported on the stimulation of clonal growth of a glioblastoma cell line by rhSCF (Berdel et al., Cancer Res 1992, 52, 3498-3502). Within an extensive screening programme of haematopoietic growth factor activity on malignant cells, the effects of rhSCF were further tested on the growth of 29 different human cell lines derived from a wide range of solid tumours, among them six lung cancers and five melanomas. RhSCF (0, 1, 10, 100 ng/ml) was tested in a human tumour cloning assay (HTCA) which reliably detects growth modulation of tumour cells by cytokines. Additionally, a tritiated thymidine uptake test was used. Growth of 27 of the 29 cell lines tested was not affected by rhSCF. However, growth of the small cell lung cancer (SCLC) cell line HTB 120 was slightly stimulated (1.5 fold that of controls), and that of the melanoma cell line MeWo was stimulated up to 1.3-fold. This activity was eliminated dose-dependently by the tyrosine kinase inhibitor, genistein. We further analysed the cell lines for expression of the proto-oncogene C-KIT and its ligand SCF. All melanoma and lung cancer cell lines expressed SCF as assessed at the mRNA level. Northern blotting also revealed clear C-KIT mRNA expression in three melanoma (HAS, MeWo, SK-MEL-28), one NSCLC (HTB 53), and four SCLC cell lines (HTB 119, HTB 120, HTB 171, HTB 175). Furthermore, C-KIT protein expression was detected by flow cytometric analysis on the cell surface of MeWo, HTB 119 and HTB 120 cells. Our data indicate that SCF can be operative in growth modulation of non-haematopoietic malignant cells, especially SCLC and melanoma. However, our extensive screening of SCF/tumour cell interaction shows that this interaction is rare and makes potential hazards, such as tumour stimulation upon clinical use of rhSCF in conjunction with chemotherapy in cancer patients, unlikely for the majority of other tumour histologies.
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PMID:Recombinant human stem cell factor does exert minor stimulation of growth in small cell lung cancer and melanoma cell lines. 865 71

The E2F element is a cis-acting DNA sequence within the P2 promoter of c-myc proto-oncogene. While it is required for optimal transcription, the multiprotein complexes formed on this site have not been well characterized. We show that in extracts of human glioblastoma cells and NIH3T3 fibroblasts, significant E2F transcription factor binding to the c-myc E2F site occurs as a both a monomer (the active form) and as only two mutually exclusive complexes with the retinoblastoma gene product (pRb) or the cyclin A protein. The E2F protein monomer was found predominantly in the cytosolic fraction of the cellular extracts while the pRb and cyclin A complexes in the nuclear fraction, indicating that the monomer has novel physical properties. Thus, protein complex formation on the c-myc E2F site appears to contribute in a unique way to transcriptional activation.
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PMID:Multiprotein complex formation on the c-myc promoter. 941 3


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