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)

We have used molecular genetic methods to examine the status of cell cycle-inhibitory genes in human brain tumors. We found that p16 and a neighboring gene, p15, were often homozygously deleted in glioblastoma multiformes but not in medulloblastomas or ependymomas. The deletions occurred in both primary tumors and their derived xenografts, but no intragenic mutations in either of the two genes were found. The p15 gene was expressed in a more widespread pattern in normal tissues than p16, but the products of both genes had similar capacities to bind to cyclin D-dependent kinases 4 and 6. These data suggest that the target of deletion in glioblastoma multiforme includes both p15 and p16 genes. The reason that homozygous deletions, rather than intragenic mutations, are so common in these tumors may be that deletion is a more efficient mechanism for simultaneous inactivation of both genes.
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PMID:Deletion of p16 and p15 genes in brain tumors. 798 28

We have investigated the status of the MTS2 gene, encoding the cyclin-dependent kinase (CDK) inhibitor p15, in 32 glioblastomas. Semi-quantitative PCR identified 7 tumors in which the amplified material was 18.6% of controls and 7 in which was 48.0%, suggesting the occurrence of homozygous and hemizygous deletions, respectively. Single strand conformation polymorphism analysis identified one polymorphism but no mutations. We also expressed MTS2 and MTS1, encoding the contiguous and highly homologous CDK inhibitor p16, in U-87 human glioblastoma cells. Both genes, either separately or in combination, inhibit significantly the proliferation rate of U-87 cells but such inhibition is progressively lost. As a whole, the data assign a tumor suppressor role to p15 and confirm homozygous deletions as the favorite mechanism for the inactivation of MTS1 and MTS2 in glioblastomas.
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PMID:Deletion and transfection analysis of the p15/MTS2 gene in malignant gliomas. 852 10

Loss of heterozygosity (LOH) observed at polymorphic loci on both arms of chromosome 10 in many human gliomas suggests the presence of multiple tumor suppressor genes on this chromosome. Recently, the PTEN/MMAC1 gene on 10q23 was isolated as one of these putative glioma suppressors. To determine the subchromosomal localization of others, we analysed 79 gliomas for LOH using 30 polymorphic microsatellite markers on the short arm and 10 markers on the long arm of chromosome 10. Twenty tumors showed LOH at all the loci examined, while 17 others showed LOH at loci on a portion of chromosome 10. Deletion mapping of the latters demonstrated that two distinct regions, encompassing genetic distances of 5.6 cM on 10p15 and 5.5 cM on 10p14, were lost frequently. Introduction of chromosomal fragments 10p14-p15, which included the entire region on 10p15 and a portion of that on 10p14 assigned by deletion mapping, into the human glioblastoma cell line T98G through microcell-mediated chromosome transfer markedly suppressed colony forming ability in soft agar compared with parental T98G cells. The combined results of structural and functional analyses strongly suggest that aberrations of the tumor suppressor gene(s) within chromosomal region 10p14-p15 are involved in development of human gliomas.
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PMID:Structural and functional evidence for the presence of tumor suppressor genes on the short arm of chromosome 10 in human gliomas. 946 44

We established two glioma cell lines from two surgical specimens obtained at different times from the same patient. One (No. 9R), which was derived from the recurrent tumor (glioblastoma, grade IV), proliferated more rapidly in vitro than the other (No. 9) from the primary tumor (slightly anaplastic astrocytoma, grade II-III). No. 9R showed heterotransplantability in nude mice, whereas No. 9 did not. These findings indicate that No. 9R has a more aggressive or malignant nature than No. 9. Both cell lines showed homozygous deletion of the representative tumor suppressor p16 and p15 genes, but no p53 gene alteration. However, examination of the overall mRNA expression profile using a commercially available cDNA-spotted membrane revealed much higher expression levels of several mRNAs, at least, in No. 9R than in No. 9, although the relationship between these mRNAs and the growth potentials remained unknown. These two cell lines, derived from the same individual, with different proliferating potentials may be useful for studies on the molecular bases of glioma malignancy and progression.
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PMID:Establishment of two glioma cell lines from two surgical specimens obtained at different times from the same individual. 1035 44

Homozygous chromosome 9p deletions in gliomas commonly include the CDKN2A and CDKN2B genes, which code for the structurally highly homologous cdk inhibitors/tumor suppressors p16 and p15, respectively. Alternative splicing of the CDKN2A gene results in the expression of p14(ARF). Interestingly, not only p16 and p15, but also the structurally unrelated p14(ARF) appear to function as negative cell cycle regulators. Concerted inactivation of p16, p15 and p14(ARF) could be demonstrated in seven of nine glioblastoma cell lines. Strong suppression of tumorigenicity after transfection with p16 and p15 alone or in combination was seen in cell lines containing neither endogenous p16 nor p15 but functional pRB. Significantly weaker growth suppression was observed in tumors either retaining expression of both p16 and p15 or p15 only. p14(ARF) proved to be a potent tumor suppressor in the presence of wild-type p53, while mutant p53 substantially reduced growth inhibition by p14(ARF). No differences between p16 and p15 effects could be observed, suggesting a largely overlapping function of p16 and p15. To facilitate further research into p16/p15 effects, three cell lines with conditional, tetracycline-controlled p16 expression were established. Reversible growth suppression mediated by p16 was observed in these models. Combined inactivation of CDKN2A and CDKN2B, i.e., loss of both p16 and p15 as well as p14(ARF), results in disruption of two major growth control pathways involving pRB and p53 in malignant gliomas. Therefore, homozygous co-deletions of CDKN2A and CDKN2B rather than mutations targeting individual transcripts are frequently selected for in these tumors.
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PMID:Functional evidence for a role of combined CDKN2A (p16-p14(ARF))/CDKN2B (p15) gene inactivation in malignant gliomas. 1054 65

Representational difference analysis (RDA) of a human glioblastoma xenograft resulted in the isolation of five tumour-associated homozygously deleted DNA fragments, all originating from chromosome 9, region p21. Subsequent analysis of a series of ten glioblastomas using the newly isolated RDA fragments in conjunction with a series of known 9p21 DNA markers revealed homozygous deletions in nine of the ten (90 per cent) tumours. These deletions encompass the p15/p16 complex and two additional putative tumour suppressor loci. The RDA fragments correspond to the latter two loci. Taken together, these results suggest the involvement of multiple tumour suppressor genes from the 9p21 region in glioblastoma tumourigenesis. The novel RDA fragments will be instrumental in the isolation of the relevant genes.
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PMID:Isolation and characterization of glioblastoma-associated homozygously deleted DNA fragments from chromosomal region 9p21 suggests involvement of multiple tumour suppressor genes. 1054 3

Thirty-four to fifty-six percent of malignant gliomas harbor homozygous co-deletions of the INK4a(p16-p14ARF) and INK4b(p15) tumor suppressor genes. Recently, an alternatively spliced form of p15 has been cloned and termed p10 based on the presumed molecular weight of the protein. In this study, we have investigated the role of p10 expression in human glioblastomas. Both, wild-type p15 and p10 were detected in three of nine glioblastoma cell lines. Sixteen of twenty-nine (55%) glioblastoma tumor samples contained INK4b transcripts, but only nine (31%) tumors expressed p15 protein. Three p15 protein-negative tumors expressed only p10 mRNA. Preferential expression of p10 was not due to splice site mutations. Strong suppression of tumorigenicity was seen in four glioblastoma cell lines after transfection with p15 but not with p10. Loss of p15 protein expression was almost always accompanied by loss of p16 expression. p1 6/p15-negative tumors commonly lacked p14ARF expression. These results suggest that differential splicing of the INK4b gene may result in the expression of p10 at the expense of p15, which would lead to loss of p15-mediated growth suppression. This novel mechanism of loss of p15 might complement alterations of the INK4a tumor suppressor gene in some glioblastomas, resulting in combined loss of p16, p15 and p14ARF.
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PMID:Alternative splicing of the p15 cdk inhibitor in glioblastoma multiforme. 1156 32

Five malignant glioma cell lines (YMG1, 2, 3, 4, and 5) were established from surgical specimens obtained from patients with glioblastoma or anaplastic astrocytoma, and these lines were partially characterized. Three glioma cell lines (YMG1, 3, and 5) were weakly positive for GFAP by Western blot analysis and two cell lines were negative. S-100 protein was positive in all glioma cell lines. The expression of p53, p16, p15, cyclin-dependent kinase 4 (CDK4), and EGF receptor (EGFR) proteins was examined by Western blotting. YMG1 and 2 cell lines showed accumulation of p53 protein and loss of p16 and p15 expression. YMG3 and 4 showed accumulation of p53 protein and expression of p16 and p15 proteins. YMG5 revealed weak expression of p53 protein, suggesting wild-type p53, and loss of p16 and p15 expression. All cell lines expressed various levels of CDK4 protein. YMG1, 2, and 3 showed higher EGFR protein expression and YMG4 and 5 showed lower EGFR expression compared to U251 glioblastoma cells, which express high levels of EGFR. Fluorescence in situ hybridization analysis for EGFR gene expression did not show any amplification in the glioma cell lines. Immunohistochemical studies revealed that the patterns of p53 and EGFR expressions in the original tumor tissues were mostly correlated with those in the malignant glioma cell lines. These results suggest that the characteristics of p53 and EGFR expression in the malignant glioma cell lines were passed over from the original tumor tissues. These newly established malignant glioma cell lines can be used for further analysis of the mechanisms of tumor growth and progression.
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PMID:Establishment and partial characterization of five malignant glioma cell lines. 1587 6

The aim of the present study was to elucidate genetic alterations that are critically involved in astrocytoma progression. We characterized 27 World Health Organization grade II fibrillary astrocytomas which later underwent recurrence or progression, paying specific attention to the CpG island methylation status of critical growth regulatory genes. p14(ARF) and O(6)-methylguanine-DNA methyltransferase (MGMT) hypermethylation represented frequent events (26% and 63%, respectively), which were mutually exclusive except in one case, with alternate or simultaneous methylation of these two genes occurring in 85% of our tumor series. Seventeen tumors (63%) contained TP53 mutations, which were closely related to the presence of MGMT methylation. Methylation of the p21(Waf1/Cip1), p27(Kip1) and p73 genes and homozygous deletion of the p16(INK4a), p15(INK4b) and p14(ARF) genes were not detected in any of the primary low-grade tumors. The presence of p14(ARF) methylation at first biopsy was associated with shorter patient survival, whereas the presence of MGMT methylation carried a better clinical outcome after salvage therapy. Examination of 20 cases whose histological data for recurrent tumors were available revealed that malignant progression occurred in all of the tumors with p14(ARF) methylation but less frequently (50%) in the lesions with MGMT methylation. On analysis of their respective recurrent tumors, five of six patients whose primary low-grade tumors carried p14(ARF) methylation exhibited homozygous co-deletions of the p14(ARF), p15(INK4b) and p16(INK4a) genes, which were restricted to glioblastoma as the most malignant end point. Our findings suggest that p14(ARF) hypermethylation and MGMT hypermethylation constitute distinct molecular pathways of astrocytoma progression, which could differ in biological behavior and clinical outcome.
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PMID:Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. 1749 32

Glioblastomas are the most frequent and malignant brain tumors in adults. Surgical cure is virtually impossible and despite radiation and chemotherapy the clinical course is very poor. Epigenetic silencing of MGMT has been associated with a better response to temozolomide-chemotherapy. We previously showed that temozolomide increases the median survival time of patients with tumors harbouring deletions on 9p within the region for p15(INK4b), p16(INK4a), and 10q (MGMT). The aim of this study was to investigate the methylation status of p15, p16, p14ARF and MGMT in glioblastomas (n=27) and to correlate the results with the clinical data. Only patients with KPS >70, radical tumor resection, radiation and temozolomide-chemotherapy after recurrence were included. We observed promoter methylation of MGMT in 56% and of p15 in 37% of the tumors, whereas methylation of p16 and p14ARF were rare. Interestingly, methylation of p15 emerged as a significant predictor of shorter overall survival (16.9 vs. 23.8 months, p=0.025), whereas MGMT promoter methylation had no significant effect on median overall survival under this treatment regimen (22.5 vs. 22.1 months, p=0.49). In the presence of other clinically relevant factors, p15 methylation remains the only significant predictor (p=0.021). Although these results need to be confirmed in larger series as well as under different treatment conditions, our retrospective study shows clear evidence that p15 methylation is an important prognostic factor for survival and underlines that this tumor suppressor, involved in cell cycle control, is an attractive candidate for therapeutic approaches in glioblastomas.
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PMID:p15 promoter methylation - a novel prognostic marker in glioblastoma patients. 1942 93


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