Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proliferative capacity of brain-tumor cells was analyzed in vitro and in situ using monoclonal antibody (MAb) against deoxyribonucleic acid (DNA) polymerase alpha. For the in vitro studies, two cultured human glioma cell lines were investigated using MAb against DNA polymerase alpha, the MAb Ki-67, a serum against proliferating cell nuclear antigen (PCNA/cyclin), bromodeoxyuridine (BUdR), and an anti-BUdR MAb. During exponential growth of the cells, the percentage of polymerase alpha-positive cells (the "polymerase alpha score") ranged from 72.0% to 77.1%, the Ki-67-positive cells (the "Ki-67 score") ranged from 43.4% to 59.4%, the PCNA/cyclin-positive cells from 30.9% to 41.4%, and the BUdR labeling index from 28.6% to 39.3%. For the in situ studies, tissue from 60 human brain tumors and from two normal human brains was investigated and the polymerase alpha scores and Ki-67 scores were compared. In normal brain tissue, no immunostaining was found by either method. In brain tumors, both the polymerase alpha scores and the Ki-67 scores correlated with the histological grade of malignancy. Polymerase alpha scores were generally higher than Ki-67 scores in the same specimen, especially in malignant brain tumors. These findings suggest that immunostaining of DNA polymerase alpha is a convenient and important new method by which to estimate the cellular proliferation rate of brain tumors. Polymerase alpha scores may be closer to the growth fraction of the individual tumor than the MAb Ki-67 or other scores.
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PMID:Immunohistochemical demonstration of DNA polymerase alpha in human brain-tumor cells. 196 2

The authors analyzed water-soluble proteins of culture human and rat glioma cells by two-dimensional polyacrylamide gel electrophoresis methods. Glioma cells were suspended in distilled water and then destroyed by freezing and thawing to obtain the water-soluble protein fraction. A modification of O'Farrell's non-equilibrium pH gradient (NEPHGE) method was used to analyze differences in protein mapping. Manabe's microscale two-dimensional electrophoresis without denaturing agents was used to detect proliferating cell nuclear antigen (PCNA/cyclin) by Western blotting. With O'Farrell's NEPHGE method and silver staining, at least 200 different polypeptides were clearly identified in each cell line. Cytoskeletal proteins, such as actin, were consistently separated in all cell lines. Marked differences in the protein map were observed between human and rat glioma cell lines, and even within the same species. Presumably, these differences are attributable to cell-biological difference in the glioma cells lines. Some proteins that were prominent in proliferating cells were scant in the protein maps of cells cultured for 24 hours in medium not containing calf serum, which suppresses cell growth. PCNA, an acidic nuclear protein that appears only in the late G1-S phase and is believed to be involved in cell proliferation, was detected by Western blotting and indirect immunostaining. Quantitative analysis of PCNA spots on the protein map appears useful in assessment of glioma cell proliferation. These results indicate that two-dimensional polyacrylamide gel electrophoresis can contribute to the understanding of the biological features of glioma cells.
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PMID:[Analysis of the water-soluble protein fraction of glioma cells by two-dimensional electrophoresis]. 247 47

Induction of apoptosis in tumor cells is an important determinant in the outcome of therapy. Molecular details of the apoptosis pathway, however, are still poorly defined. The recently discovered WAF1/CIP1 gene is a potent inhibitor of cyclin-dependent kinases and a mediator of tumor-suppressor p53-dependent apoptosis by DNA damage. In addition, WAF1/CIP1 expression is shown to be triggered through the p53-independent pathway. The relationship between WAF1/CIP1 and p53-independent apoptosis by DNA damage, however, remains unclear. In this study, we show that WAF1/CIP1 was induced in p53-dependent apoptosis of U87-MG glioma cells by cis-diamminedichloroplatinum (cisplatin), and overexpression of WAF1/CIP1 induced apoptosis in U87-MG cells without cisplatin treatment. In contrast, the p53-independent apoptosis of GB-1 glioma cells by cisplatin did not express WAF1/CIP1. Overexpression of WAF1/CIP1 inhibited DNA synthesis in GB-1 cells, but did not induce apoptosis. Interestingly, WAF1/CIP1 increased the susceptibility of GB-1 cells to cisplatin-induced apoptosis. These results suggest that overexpression of WAF1/CIP1 may have potential for the treatment of tumors with non-functional p53.
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PMID:WAF1/CIP1 increases the susceptibility of p53 non-functional malignant glioma cells to cisplatin-induced apoptosis. 880 2

Cyclin D1 plays a key regulatory role during the G1 phase of the cell cycle and its gene is amplified and overexpressed in many cancers. To address the relationship between cyclin D1 and other cell cycle regulatory proteins, we established human glioma and rodent fibroblast cell lines in which cyclin D1 expression could be regulated ectopically with tetracycline. In both of these cell lines, we found that ectopic expression of cyclin D1 in asynchronously growing cells was accompanied by increased levels of the p53 tumor suppressor protein and the cyclin/cdk inhibitor p21. Despite the induction of these cell cycle inhibitory proteins, cyclin D1-associated cdk kinase remained activated and the cells grew essentially like that of the parent cells. Although growth parameters were unchanged in these cells, morphological changes were clearly identifiable and anchorage independent growth was observed in NIH3T3 cells. In a first step toward elaborating the mechanism for cyclin D1-mediated induction of p21 gene expression we show that co-expression of E2F-1 and DP-1 can specifically transactivate the p21 promoter. In support of these findings and a direct effect of E2F on induction of p21 gene expression a putative E2F binding site was identified within the p21 promoter. In summary, our results demonstrate that ectopic expression of cyclin D1 can induce gene expression of the cdk inhibitor p21 through an E2F mechanism the consequences of which are not to growth arrest cells but possibly to stabilize cyclin D1/cdk function.
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PMID:Regulated ectopic expression of cyclin D1 induces transcriptional activation of the cdk inhibitor p21 gene without altering cell cycle progression. 919 Oct 53

We have previously described a dramatic phenomenon of phenotypic reversion (tumor to normal) caused by glucocorticoid hormones in C6/ST1 rat glioma cells, but not in their hormone-resistant C6/P7 counterpart. Blind cDNA cloning was adopted to search for glucocorticoid-regulated gene sequences responsible for this phenotype reversion. Differential hybridization and differential display of RNA were used in parallel to isolate a number of cDNA clones that were characterized by DNA sequencing and Northern blot analysis. This approach was coupled to the analysis of known growth control genes (oncogenes, tumor suppressor genes, cyclins, cyclin-dependent kinases, other kinases). Glucocorticoid target genes isolated from this cell system are likely to be good anti-tumor candidate molecules which can be used in tumor therapy and anti-tumor drug design.
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PMID:Use of cDNA cloning to study the mechanism of action of glucocorticoid hormones at the molecular level. 922 40

p21WAF1/CIP1 is a downstream mediator of p53 and mediates growth arrest by inhibiting the action of G1 cyclin-dependent kinases. Since cellular differentiation is frequently characterized by G1 arrest, we examined whether p21WAF1/CIP1 overexpression would induce growth suppression and differentiation in p53-defective human glioma cells. Overexpression of p21WAF1/CIP1 resulted in an accumulation of cells in G1, altered morphology, growth arrest and cell differentiation. The extent of cell differentiation correlated with the level of p21WAF1/CIP1 as well as of proliferating cell nuclear antigen, cyclin E, and cdk 2, which associates with p21WAF1/CIP1. Our data suggest that gene transfer of p21WAF1/CIP1 may arrest glioma cell growth in vivo by committing malignant glioma cells to a pathway of terminal differentiation.
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PMID:Overexpression of p21WAF1/CIP1 induces cell differentiation and growth inhibition in a human glioma cell line. 946 69

This review examines the apparently paradoxical conversion of transforming growth factor beta's (TGFbeta) regulatory role as a growth inhibitor among normal glial cells to that of a progression factor among glioblastomas (GM). In vitro, TGFbeta functions as an autocrine growth inhibitor of near-diploid gliomas of any grade. In contrast, hyperdiploid glioblastoma multiforme (HD-GM) cultures proliferate in response to TGFbeta, which is mediated by induction of platelet-derived growth factor B chain (PDGF-BB). The dominant hypothesis of TGFbeta's pathogenetic association with malignant transformation has been predicated upon acquisition of resistance to its growth inhibitory effects. However, the lack of obvious correlation with TGFbeta receptor (TbetaR) expression (or loss) between the HD-GM and the TGFbeta-inhibited GM cultures suggests the existence of intrinsically opposed regulatory mechanisms influenced by TGFbeta. The mechanism of conversion might be explained either by the loss of a putative tumor suppressor gene (TSG) which mediates TGFbeta's inhibition of growth or by enhancement of an active oncogenic pathway among the HD-GM. The frequency of mutations within glioma-associated TSG, such as TP53 and RB, suggests that defects in TGFbeta's inhibitory signaling pathway may have analogous effects in the progression to HD-GM, and TGFbeta's conversion to a mitogen. Alternative sites of inactivation which might explain the loss of TGFbeta's inhibitory effect include inactivating mutation/loss of the TbetaR type II, alterations in post-receptor signal transmission or the cyclin/cyclin dependent kinase system which regulates the phosphorylation of pRB. Loss or inactivation of a glial TSG with a consequent failure of inhibition appears to allow TGFbeta's other constitutive effects, such as induction of c-sis, to become functionally dominant. Mechanistically, TGFbeta's conversion from autocrine inhibitor to mitogen promotes 'clonal dominance' by conferring a Darwinian advantage to the hyperdiploid subpopulations through qualitative and quantitative differences in its modulation of PDGF-A and c-sis, with concomitant paracrine inhibition of competing, near-diploid elements.
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PMID:The role of transforming growth factor beta in glioma progression. 952 12

p27/kip-1 is a 'universal inhibitor' which inhibits cyclin complexes with cyclin-dependent kinases (CDKs), preventing cell cycle from the G1-S progression. It is expressed in normal oligodendrocytes and in differentiated glial tumors, decreasing with anaplasia and malignancy. In non-astrocytic and non-oligodendrocytic tumors of the nervous system, such as meningiomas, schwannomas, medulloblastomas, neuroblastomas and malignant lymphomas, p27/kip-1 is inconstantly and sometimes poorly expressed. This can be due to the lacking of p27 expression in the normal counterpart of tumor cells. In some tumors, p27/kip-1 expression can be attributed to a differentiation process, as in the pale islands of desmoplastic medulloblastoma and in neuroblastomas. A correlation of p27/kip-1 expression with histology was not found, with the exception of apoptosis in medulloblastomas. p27/kip-1 is in feed-back with cyclins and CDKs for the control of cell proliferation and its expression may occur where requested by the interplay with cyclins and other inhibitors.
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PMID:Cell-cycle inhibitor p27/Kip-1 expression in non-astrocytic and non-oligodendrocytic human nervous system tumors. 1032 6

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
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PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66

Malignant gliomas frequently show genetic aberrations of genes coding for cell cycle regulatory proteins involved in the control of G1/S phase transition. These include mutation and/or deletion of the retinoblastoma (RB1) gene, homozygous deletion of the CDKN2A and CDKN2B genes, as well as amplification and overexpression of the CDK4 and CDK6 genes. The D-type cyclins (cyclin D1, D2, and D3) promote cell cycle progression from G1 to S phase by binding to and activating the cyclin dependent kinases Cdk4 and Cdk6. Here, we have investigated a series of 110 primary malignant gliomas and 8 glioma cell lines for amplification and expression of the D-type cyclin genes CCND1 (11q13), CCND2 (12p13), and CCND3 (6p21). We found the CCND1 gene amplified and overexpressed in one anaplastic astrocytoma of our tumor series. Two glioblastomas and one anaplastic astrocytoma showed CCND2 gene amplification, but lacked significant overexpression of CCND2 transcripts. Amplification and overexpression of the CCND3 gene was detected in the glioblastoma cell line CCF-STTG1, as well as in one primary glioblastoma and in the sarcomatous component of one gliosarcoma. Our data thus suggest that amplification and increased expression of CCND1 and CCND3 contribute to the loss of cell cycle control in a small fraction of human malignant gliomas.
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PMID:Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. 1041 84


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