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)

Platelet-derived growth factor (PDGF) is a basic protein of relative molecular mass 30,000 (Mr 30K) composed of two polypeptide chains, designated PDGF A and PDGF B. The B-chain is encoded by the c-sis gene, the cellular counterpart of the simian sarcoma virus transforming gene v-sis. The PDGF A-chain cDNA clones recently isolated and sequenced from a transformed human clonal glioma cell line represent at least two alternatively spliced transcript species differing by 69 base pairs at the C-terminus. Here we demonstrate that the normal human umbilical vein endothelial cell (EC) A chain precursor lacks the 15 carboxy-terminal, highly basic amino acids encoded by the larger tumour cell cDNA. Surprisingly, culture media from monkey kidney cells (COS) transfected with the endothelial cDNA clone contained much less mitogenic activity than media from cells transfected with the longer tumour cell-derived A-chain cDNA. This functional difference appeared to be due to inefficient assembly or secretion of the recombinant endothelial-type growth factor. This suggests that some transformed cells may use alternative RNA splicing to modify normal growth factors and by so doing increase the efficiency of mitogen assembly or secretion.
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PMID:Alternative RNA splicing affects function of encoded platelet-derived growth factor A chain. 361 64

The protein encoded by c-sis is overexpressed in human neuroglial tumors and has been hypothesized to play an important role in tumorigenesis. To address this issue, we examined the effect of an 18-base pair oligodeoxynucleotide complementary to a sequence starting of ATG initiation codon of mRNA of c-sis upon glioma cell growth. First, we investigated the expression of c-sis within cultured human glioma cell lines and also fresh glioma specimens by using polymerase chain reaction. We could detect messenger ribonucleic acid transcripts of c-sis in three of four glioma cell lines and two of five glioblastoma multiforme specimens. This finding was confirmed by dot-blot hybridization with a specific oligonucleotide probe of c-sis. The antisense oligonucleotides complementary to c-sis messenger ribonucleic acid were efficiently incorporated into A172 cells in vitro, and kinetic studies showed that maximum uptake was seen after 48 hours incubation with antisense oligomers. Exposure of human glioma cell lines to antisense oligodeoxynucleotides targeted against the first initiation codon of c-sis inhibited cell proliferation in a time- and dose-dependent fashion. From flow cytometric analysis with anti-c-sis sera, it was demonstrated that the antisense oligomers specifically block the de novo synthesis of intracellular c-sis protein by glioma cells. In contrast, the corresponding sense oligomers did not inhibit either synthesis of c-sis protein or glioma cell growth. These results clearly support a role of c-sis protein in the proliferation of these human neuroglial tumors and show that inducible protein expression can be blocked by means of synthetic oligonucleotides complementary to a coding exon.
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PMID:Specific inhibition of c-sis protein synthesis and cell proliferation with antisense oligodeoxynucleotides in human glioma cells. 817 92

Among early-passage, near-diploid gliomas in vitro, transforming growth factor type beta (TGF beta) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (> or = 57 chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGF beta. The mechanism of this 'conversion' from autocrine inhibitor to mitogen is not understood; previous studies have suggested that platelet-derived growth factor (PDGF) might be modulated by TGF beta. The similar expression of TGF beta types 1-3, PDGF-AA; -BB, as well as the PDGF receptor alpha and beta subunits (a/beta PDGFR) between biopsies of the HD-GM and near-diploid, TGF beta-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flow cytometry demonstrated that TGF beta's mitogenic effect was selective for the aneuploid subpopulations of two of three selected HD-GM cultures, while the diploid cells were inhibited. Among the HD-GM, TGF beta 1 induced the RNA of PDGF-A, c-sis and TGF beta 1. The amount of PDGF-AA secreted following TGF beta treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BB, -AB, alpha PDGFR and/or beta PDGFR subunits effectively neutralized TGF beta's induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGF beta's growth stimulatory effect. By comparison, TGF beta induced only the RNA of PDGF-A and TGF beta 1 among the near-diploid GM, c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to TGF beta 1 was insufficient to prevent TGF beta's arrest of the near-diploid cultures in G1 phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGF beta's modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cells might achieve 'clonal dominance'. We hypothesize that TGF beta may serve as an autocrine promoter of GM progression by providing a selective advantage to the hyperdiploid subpopulation through the loss of a tumor suppressor gene which mediates TGF beta's inhibitory effect.
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PMID:Transforming growth factor beta as a potential tumor progression factor among hyperdiploid glioblastoma cultures: evidence for the role of platelet-derived growth factor. 904 53

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

BACKGROUND: Antisense oligodeoxynucleotides (ODNs) have been proposed as a new therapy for patients with cancer, including malignant brain tumors. Antisense ODNs are taken up by tumor cells and selectively block gene expression. Use of ODNs for brain tumors is attractive due to their theoretical specificity, relative ease of production and, to date, paucity of reported adverse effects. This article presents current information regarding antisense ODNs and their possible future use for the treatment of brain tumors. METHODS: The available published experimental and clinical information regarding antisense ODN treatment of glioblastoma cells and administration into the central nervous system (CNS) was reviewed. Other clinically relevant information pertaining to the molecular biology of antisense ODNs was also collected and summarized. RESULTS: Targets for antisense ODN therapy in malignant glioma cells have included c-myc, c-myb, c-sis, c-erb B, CD44, p34cdc2, bFGF, PDGF, TGF-beta, IGF-1, PKC-alpha tumor necrosis factor, urokinase, and S100beta protein. Few in vivo studies of ODN treatment of brain tumors have yet been reported. Systemically administered ODNs enter the brain only in extremely small quantities; therefore, microinfusion into the brain has been recommended. CONCLUSIONS: Antisense ODNs have been used successfully to block glioblastoma gene expression in vitro and expression of multiple genes within the CNS of experimental animals. Upcoming clinical trials will address the safety of antisense ODN use against malignant brain tumors.
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PMID:Antisense Oligodeoxynucleotide Technology: Potential Use for the Treatment of Malignant Brain Tumors. 1076 Oct 27

Growth factor/ligand interactions have been shown to play an important role in various malignancies. Expression of two differentially spliced forms of SCF was detected in 20 of 24 glioma cell lines by RT-PCR. Northern blot analysis revealed expression of the corresponding receptor, c-kit (11/24), as well as PDGF alpha-receptor (22/25 glioma cell lines), PDGF beta-receptor (22/25), TGF-alpha (13/24 ) and PDGF B/c-sis (7/16) expression. As determined by FACS analysis, expression of EGFR and p185HER2 was detected in 21 of 21 and 15 of 21 glioma cell lines, respectively. Four cell lines showed moderate EGFR overexpression (>90,000 receptors/cell) and in one cell line p 185HER2 expression exceeded EGFR levels. Loss of EGFR gene amplification during in vitro culturing was observed in 3 of 18 investigated cell lines by differential PCR. In summary, our work suggests the simultaneous activation of several different growth factor/receptor systems in human glioma cell lines.
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PMID:Protooncogene expression in human glioma derived cell-lines. 2158 98


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