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)

Heat shock induces several events in cells including a series of gene expressions and cell cycle arrest. Recently, several types of cell cycle arrest have been related to the function of cyclin-dependent kinase inhibitors (CKI). Here we show that heat shock treatment up-regulates p21 CKI mRNA and protein in A172 glioma cells and arrests the cell cycle at the G1 phase, p53-deficient cell lines, MDAH041 and T98G, also showed a significant increase in p21 CKI expression after heat stress, indicating that the induction involves a p53-independent pathway. The kinetics of this transient induction, which is not affected by cycloheximide, demonstrate that p21 CKI is an immediate-early response gene.
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PMID:Heat shock-mediated cell cycle arrest is accompanied by induction of p21 CKI. 878 Jun 86

Telomerase, the enzyme that elongates telomeric DNA (TTAGGG)n, may be involved in cellular immortality and oncogenesis. To investigate the effect of inhibition of telomerase on tumor cells, we transfected the antisense vector against the human telomerase RNA into human malignant glioma cells exhibiting telomerase activity. After 30 doublings, some subpopulations of transfectants expressed a high level of interleukin-1beta-converting enzyme (ICE) protein and underwent apoptosis. In contrast, other subpopulations also showed enhanced ICE protein but escaped from apoptotic crisis and continued to grow, although their DNA synthesis, invasive ability, and tumorigenicity in nude mice were significantly reduced. Surviving cells demonstrated increased expression of glial fibrillary acidic protein and decreased motility, consistent with a more differentiated state. These cells also contained enhanced expression of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27. Treatment of surviving nonapoptotic cells with antisense oligonucleotides against p27, but not p21, induced apoptotic cell death, suggesting that p27 may have protected differentiating glioma cells from apoptosis. These data show that treatment with antisense telomerase inhibits telomerase activity and subsequently induces either apoptosis or differentiation. Regulation of these two distinct pathways may be dependent on the expression of ICE or CDKIs.
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PMID:Antisense telomerase treatment: induction of two distinct pathways, apoptosis and differentiation. 965 20

We have recently shown that glioma cell lines, as well as cells of human malignant gliomas in situ, synthesize tropoelastin. In addition, glioma cells degrade tropoelastin using metalloproteinase(s), and the resulting peptides, incapable of assembling in the extracellular fibers, interact with the 67-kDa cell surface elastin binding protein (EBP), to transduce signals leading to up-regulation of cell proliferation. In this report, we show that exposure to the polysulfonated bis-naphthylurea suramin causes accumulation of physiologically active EBP molecules on the cell surface of a panel of glioma cell lines (U87, MG, U251 MG, U343 MG-A, U373 MG, SF 126, SF188, SF539), which results in an increase of cellular attachment to elastin-coated dishes and in an efficient binding of radiolabeled tropoelastin. Moreover, 100-200 microM suramin stimulates [3H]-thymidine incorporation by those tropoelastin-producing glioma cell lines, but not by A 2058 melanoma cells, which do not produce elastin. Treatment of all glioma cell lines with 100 microM suramin consistently increased expression of cyclin A and its cyclin-dependent kinase, cdk 2, to levels reached following the exposure to exogenous elastin-degradation products (kappa-elastin). Our data suggest that a suramin-stimulated accumulation of EBP molecules on the cell surface of glioma cells amplifies the elastin-derived signals, leading to their progression through the cell cycle.
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PMID:Cell surface aggregation of elastin receptor molecules caused by suramin amplified signals leading to proliferation of human glioma cells. 1020 80

C6 glioma - Ca2+ depletion - proliferation arrest morphology change - CDK inhibitor In this study, we investigated the role of the intracellular calcium store in modulating the cellular proliferation and the expression of cell cycle regulatory proteins in cultured C6 glioma cells. By means of microspectrofluorimetry and Ca(2+)-sensitive indicator fura-2, we found that the intracellular Ca2+ pump inhibitors, thapsigargin (TG) irreversibly and 2,5-ditert-butyl-hydroquinone (DBHQ) reversibly depleted the Ca(2+)-store accompanied with the induction of G0/G1 arrest, an increase in glial fibrillary acidic protein (GFAP) expression and morphological changes from a round flat shape to a differentiated spindle-shaped cell. The machinery underlying these changes induced by Ca(2+)-store depletion was investigated. The results indicated that Ca(2+)-store depletion caused an increased expression of p21 and p27 proteins (cyclin-dependent kinase inhibitors), with unchanged mutant p53 protein of C6 cells but reduced amounts of the cell cycle regulators: cyclin-dependent kinase 2 (CDK2), cdc2, cyclin C, cyclin D1, cyclin D3 and proliferating cell nuclear antigen (PCNA) in a time-dependent manner. These findings indicate a new function of the endoplasmic reticulum (ER) Ca2+ store in regulating cellular proliferation rate through altering the expression of p21 and p27 proteins. Moreover, cellular differentiation as revealed by spindle-shaped morphology and induced GFAP expression were also modulated by the ER Ca2+ store. The implication of this finding is that the abnormal growth of cancer cells such as C6 glioma cells may be derived from a signalling of the ER which can be manipulated by depleting the Ca2+ store.
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PMID:Proliferation arrest and induction of CDK inhibitors p21 and p27 by depleting the calcium store in cultured C6 glioma cells. 1060 59

Germ-line mutations in the p16/CDKN2 gene are known to predispose to melanoma. This gene belongs to a family of cyclin-dependent kinase inhibitors and blocks G1-S progression. The occurrence of p16/CDKN2 germline mutations in 12 Icelandic melanoma kindreds (kindreds with two or more cases of melanoma or melanoma, pancreas and/or glioma cases) was examined. No germ-line mutation was found, however five mutations not previously discribed in solid tumours were identified, Pro48Leu, Ala57Val, Gly89Asp, Leu117Met, Tyr129Stop.
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PMID:Five novel somatic CDKN2/p16 mutations identified in melanoma, glioma and carcinoma of the pancreas. Mutations in brief no. 170. Online. 1065 84

Protein kinase C (PKC) plays an important role in the regulation of glioma growth; however, the identity of the specific isoform and mechanism by which PKC fulfills this function remain unknown. In this study, we demonstrate that PKC activation in glioma cells increased their progression through the cell cycle. Of the six PKC isoforms that were present in glioma cells, PKC alpha was both necessary and sufficient to promote cell cycle progression when stimulated with phorbol 12-myristate 13-acetate. Also, decreased PKC alpha expression resulted in a marked decrease in cell proliferation. The only cell cycle-regulatory molecule whose expression was rapidly altered and increased by PKC alpha activity was the cyclin-cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1). Coimmunoprecipitation studies revealed that p21(Waf1/Cip1) upregulation was accompanied by an incorporation of p21(Waf1/Cip1) into various cyclin-CDK complexes and that the kinase activity of these complexes was increased, thus resulting in cell cycle progression. Furthermore, depletion of p21(Waf1/Cip1) by antisense strategy attenuated the PKC-induced cell cycle progression. These results suggest that PKC alpha activity controls glioma cell cycle progression through the upregulation of p21(Waf1/Cip1), which facilitates active cyclin-CDK complex formation.
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PMID:Involvement of p21(Waf1/Cip1) in protein kinase C alpha-induced cell cycle progression. 1084 85

The genes encoding the cyclin-dependent kinase inhibitors p16INK4A (CDKN2A) and p15INK4B (CDKN2B) are frequently homozygously deleted in a variety of tumor cell lines and primary tumors, including glioblastomas in which 40-50% of primary tumors display homozygous deletions of these two loci. Although the role of p16 as a tumor suppressor has been well documented, it has remained less well studied whether p15 plays a similar growth-suppressing role. Here, we have used replication-defective recombinant adenoviruses to compare the effects of expressing wild-type p16 and p15 in glioma cell lines. After infection, high levels of p16 and p15 were observed in two human glioma cell lines (U251 MG and U373 MG). Both inhibitors were found in complex with CDK4 and CDK6. Expression of p16 and p15 had indistinguishable effects on U251 MG, which has homozygous deletion of CDKN2A and CDKN2B, but a wild-type retinoblastoma (RB) gene. Cells were growth-arrested, showed no increased apoptosis, and displayed a markedly altered cellular morphology and repression of telomerase activity. Transduced cells became enlarged and flattened and expressed senescence-associated beta-galactosidase, thus fulfilling criteria for replicative senescence. In contrast, the growth and morphology of U373 MG, which expresses p16 and p15 endogenously, but undetectable levels of RB protein, were not affected by exogenous overexpression of either inhibitor. Thus, we conclude that overexpression of p15 has a similar ability to inhibit cell proliferation, to cause replicative senescence, and to inhibit telomerase activity as p16 in glioma cells with an intact RB protein pathway.
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PMID:Adenovirus-mediated overexpression of p15INK4B inhibits human glioma cell growth, induces replicative senescence, and inhibits telomerase activity similarly to p16INK4A. 1093 91

DNA damage produces delayed mitosis (G2/M delay) in proliferating cells, and shortening the delay sensitizes human malignant glioma and medulloblastoma cells to cytotoxic chemotherapy. Although activation of the cyclin-dependent kinase CDC2 mediates G2/M transition in all tumor cells studied to date, regulation of CDC2 varies between tumor types. Persistent hyperphosphorylation of kinase and reduced cyclin expression have been implicated as mediators of treatment-induced G2 delay in different tumor models. To evaluate regulation of G2/M transition in human brain tumors, we studied the expression and/or activity of CDC2 kinase and cyclins A and B1 in U-251 MG and DAOY medulloblastoma cells after their treatment with camptothecin (CPT). Synchronized cells were treated during S phase, then harvested at predetermined intervals for evaluation of cell cycle kinetics, kinase activity mRNA, and protein expression. CPT produced G2 delay associated with decreased CDC2 kinase activity and cyclin B1 expression. Kinase activity was associated with CDC2 bound to cyclin B1, not cyclin A, in both cell lines. Cyclin A mRNA and protein expression were reduced after CPT treatment; however, decreased protein expression was short lived and moderate in the glioma and primitive neuroectodermal tumor/medulloblastoma cells, respectively. We conclude that G2 delay is a common response of brain tumor cells to chemotherapy with topoisomerase I inhibitors and that a mechanism of this delay may be reduced expression of cyclin B1.
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PMID:Decreased cyclin B1 expression contributes to G2 delay in human brain tumor cells after treatment with camptothecin. 1130 12

The therapeutic efficacy of standard cancer treatments such as chemotherapy may be improved if they are combined with gene-therapy. Less than 30% of patients with glioblastoma multiforme respond to adjuvant chemotherapy. Actively dividing cells are generally more sensitive to chemotherapy than are non-dividing cells. To determine whether forced cell-cycle progression selectively sensitizes tumor cells to alkylating agents, we examined the effects of overexpressing the E2F-1 protein (a positive regulator of cell-cycle progression) on the sensitivity of two malignant human glioma cell lines, U-251 MG and D-54 MG, to BCNU and temozolomide. Treating these cells with 20-35 microM BCNU or 20-30 microM temozolomide resulted in 50% growth inhibition (IC50) within 4 or 6 days, respectively. By contrast, cells that were first induced to overexpress E2F-1 protein by infection with an adenoviral vector had IC50s that were 37-50% lower. Conversely, transferring the cyclin-dependent kinase inhibitors p16 and p21 to the cells, also by adenoviral infection, produced 3 to 4-fold increases in chemoresistance. Cell-cycle analyses showed that the combination of E2F-1 overexpression and treatment with BCNU or temozolomide increased the proportion of cells in S phase, but the combination of p16 or p21 overexpression and drug treatment reduced the proportion of cells in S phase. These observations suggest that overexpression of genes that positively control cell-cycle progression may be useful for increasing the sensitivity of glioma cells to alkylating agents.
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PMID:Adenovirally-mediated transfer of E2F-1 potentiates chemosensitivity of human glioma cells to temozolomide and BCNU. 1144 52

Human glioma cell lines differ in their requirement for the inhibition of protein synthesis to activate the CD95-dependent killing pathway. CD95 ligand (CD95L) induced mitochondrial cytochrome c release and processing of caspases 3, 7, 8 and 9 in LN-18 cells in the absence of an inhibitor of protein synthesis, cycloheximide (CHX). These biochemical changes were observed in LN-229 cells only in the presence of CHX. The viral caspase inhibitor, cytokine response modifier (crm)-A, inhibited mitochondrial cytochrome c release, caspase processing and cell death under all conditions. Ectopic expression of BCL-X(L) prevented processing of caspase 8 in LN-18 cells but not in LN-229 cells. Thus, caspase 8 activation is amplified through the release of cytochrome c in LN-18 cells but occurs mainly at the receptor in LN-229 cells. In contrast to BCL-2, BCL-X(L), X-linked inhibitor-of-apoptosis protein (XIAP) and FLICE-inhibitory protein (FLIP), the levels of the cyclin-dependent kinase (CDK) inhibitor, p21Waf/Cip1, rapidly decreased in response to CHX. P21 antisense oligonucleotides promoted caspase activation and mitochondrial cytochrome c release and induced strong sensitization to CD95-mediated apoptosis. These data place potentiating effects of CHX (i) to the activation of caspase 8 at the receptor in LN-229 cells as well as (ii) to a down-stream target at least in LN-18 cells, but probably both cell lines, that may be identical with p21Waf/Cip1.
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PMID:Identification of p21 as a target of cycloheximide-mediated facilitation of CD95-mediated apoptosis in human malignant glioma cells. 1152 Nov 88


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