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)

Induction of apoptosis in tumor cells is an important mechanism of chemotherapy-induced cell death. The tumor-suppressor gene p53 is required for the efficient activation of apoptosis following chemotherapy. However, the molecular mechanism regulating p53-associated apoptosis remains controversial. In this study, we show that the expression of both wild-type p53 and MDM2 (murine double minute 2) proteins was induced when cis-diamminedichloroplatinum (cisplatin) caused apoptosis in human glioblastoma U87-MG cells, which expressed neither wild-type p53 nor MDM2 protein prior to treatment. Overexpression of MDM2 in U87-MG cells transfected with human mdm2 expression vector conferred the resistance of tumor cell to cisplatin-induced apoptosis. In contrast, the treatment with mdm2 antisense oligonucleotide targeted against mdm2 mRNA increased the susceptibility of tumor cells to apoptosis. Changes in expression level of MDM2 protein, however, did not affect the expression of wild-type p53 protein. These findings suggest that MDM2 protein may act as a negative regulator of cisplatin-induced apoptosis, and moreover, may play an important role in the development of resistance to cisplatin in human tumors.
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PMID:MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. 776 Nov

Wild-type p53 functions in the G1 DNA damage checkpoint pathway by activating gene transcription and preventing cell cycle progression. Others reported that mutation of the serine 386 codon in mouse p53 abolished its ability to suppress growth. Serine 386 of murine p53 and the homologous residue of human p53, serine 392, are phosphorylated in vivo and can be phosphorylated in vitro by casein kinase II (CKII). We constructed mutants that changed serine 392 of human p53 to alanine (p53-S392A) or aspartic acid (p53-S392D); cotransfection of both these mutants with a reporter gene carrying a p53-responsive element into the p53-null Saos-2 cell line activated transcription as well as did wild-type p53. Furthermore, both mutants blocked cell cycle progression after transient transfection in these cells. A stable derivative of the T98G human glioblastoma cell line was established that expressed p53-S392A in response to dexamethasone. Overexpression of this mutant activated transcription of the endogenous waf1 (also called cip1) and mdm2 genes to the same extent as wild-type p53 and also produced growth arrest. Finally, p53-S392A and p53-S392D suppressed foci formation by activated ras and adenovirus E1A oncogenes as efficiently as did wild-type p53. Thus, unlike mutants that altered the serine 15 phosphorylation site, elimination of the serine 392 phosphorylation site had no discernible effect on p53 function. We conclude that neither phosphorylation nor RNA attachment to serine 392 are required for human p53's ability to suppress cell growth or to activate transcription in vivo.
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PMID:The carboxy-terminal serine 392 phosphorylation site of human p53 is not required for wild-type activities. 793 49

Chromosome 17p has been shown to be an early and frequent target for loss of heterozygosity through mitotic recombination in astrocytomas. These losses are frequently accompanied by point mutations in the p53 gene of the remaining allele, resulting in loss of wild type p53 function. However, a fraction of astrocytomas retain constitutional heterozygosity and do not have p53 mutations; some of these lose wild type p53 activity through binding to the protein product of amplified mdm2 genes. To test whether loss of wild type p53 biological function is a necessary step in astrocytoma progression we analyzed p53 expression and biological function in 13 glioma cell lines. All the cell lines expressed a 2.8-kilobase p53 transcript and showed various amounts of p53 protein by immunoprecipitation, except for cell line LN-Z308 which had only a small truncated p53 mRNA and no protein expression. To test whether the p53 expressed in these cell lines was functionally wild type or mutant we transfected them with a plasmid construct harboring a chloramphenicol acetyltransferase (CAT) reporter gene under the control of transcriptional elements that are induced by wild type but not mutant p53. Four lines were shown to retain wild type p53 function. Sequencing of the p53 gene in two of these cell lines confirmed the wild type genotype. These results show that inactivation of the p53 gene is not an obligatory step in glioblastoma genesis. This suggests either that two pathways (p53 inactivation dependent or independent) may lead to a tumor group classified histologically as glioblastoma or that in some cases p53 mutations are bypassed due to the presence of mutations in downstream effector genes.
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PMID:Analysis of the p53 gene and its expression in human glioblastoma cells. 830 26

The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumours. The mechanism by which mdr1 gene and P-gp are overexpressed in human tumours, however, is not yet clear. In this report, we show that the mdm2 (murine double minute 2) gene induced the expression of the mdr1 gene and P-gp in human glioblastoma U87-MG cells, which did not express the MDM2 protein or P-gp. The mdm2 gene, in addition, conferred the resistance of U87-MG cells to the apoptotic cell death induced by etoposide (VP-16) or doxorubicin. Furthermore, treatment with mdm2 antisense oligonucleotides inhibited the expression of P-gp in MDM2-expressing U87-MG cells. These findings suggest that the mdm2 gene may play an important role in the development of MDR phenotype in human tumours.
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PMID:mdm2 gene mediates the expression of mdr1 gene and P-glycoprotein in a human glioblastoma cell line. 888 15

P16 and P14ARF are two tumor suppressors encoded by the locus ink4a-arf which is frequently deleted in human tumors. Recent experiments performed with mouse embryonic fibroblasts have shown that P14ARF is an upstream regulator of the P53 pathway. This raises the question as to whether in human tumors the loss of p14arf and mutation of p53 are mutually exclusive events which segregate with genetic alterations at other loci. To examine this question we performed a multigenic analysis on 29 gliomas. We analysed p53 and p14arf in relation with five other genetic loci encoding the most frequently mutated genes in human gliomas: cdkn2a, mdm2, egfr, pten and the chromosomal regions 10q23.3 and 10q25-26. Our study shows for the first time that p53 mutations and p14arf deletions appear mutually exclusive in human glioblastoma, suggesting that they may be functionally redundant in glioma tumorigenesis. The P53 pathway is, therefore, disrupted in 81.8% of malignant gliomas (WHO grades III and IV), either by mutation of the p53 gene (31.8%) or by p14arf deletion (54.5%). These tumors further showed MDM2 overexpression (9.1%), egfr oncogene amplification/egfr overexpression (50%), pten mutations (27.3%) and loss of heterozygosity (LOH) at the chromosomal regions 10q23.3 (86.4%) and 10q25-26 (100%). These alterations did not segregate with p53 mutations or p14arf deletions, while p14arf and cdkn2a were always deleted.
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PMID:p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. 1094 38

To examine the functional role of tumor suppressor p53 in radiosensitivity of glioblastoma multiforme cells, I analyzed radiosensitivity of three glioblastoma cell lines with different p53 statuses: LN444 (wild-type p53), U251MG (mutant R273Q), and LN382 (mutant V197L). The mutant V197L is a temperature-sensitive (ts) mutant, of which transcriptional activity is almost normal at 34 degrees C but lost at 37 degrees C in yeast p53 functional assay. Transcriptional activity V197L p53 on mdm2, p21/WAF1, and Bax promoters determined by a luciferase assay increased respectively by 6.5, 33.4, and 4.9 folds at 34 degrees C, compared to those at 37 degrees C. Semiquantitative multiplex RT-PCR showed a slight increase of Bax mRNA expression at 34 degrees C but a marked increase of p21 mRNA expression, indicating that this ts mutant restored transcriptional activity predominantly on p21 promoter at the permissible temperature. Corresponding to the p21 transactivation, growth of LN382 cells was completely arrested without apoptosis when cultured at 34 degrees C but this arrest was reversed at 37 degrees C with a delay time subsequently to 24 or 48 h of culture at 34 degrees C. Clonogenic assay showed that dose-dependent radiosensitivity of LN382 cells to gamma-irradiation was markedly enhanced at 34 degrees C compared to that at 37 degrees C, whereas those of LN444 and U251MG were not changed between 34 and 37 degrees C. This sensitization was not attributable to apoptosis induction, since no DNA ladder formation nor sub-G1/0 phase cells were observed. Instead, cell cycle analysis demonstrated G1 and G2M arrest of the LN382 cells cultured at 34 degrees C after irradiation. In agreement to this, an increase of p21 expression was further enhanced by irradiation. In conclusion, these findings altogether suggest that p21 expression by restoration of p53 function can increase the radiosensitivity of glioblastoma cells by arresting the cells at G1 and G2M phases.
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PMID:[Functional restoration of tumor suppressor p53 alters susceptibility of glioblastoma cells to irradiation--analysis using a cell line containing a temperature-sensitive mutant]. 1097 6

Glioblastoma is the commonest neuroectodermal tumor and the most malignant in the range of cerebral astrocytic gliomas. The prognostic utility of various biological markers for glioblastomas has been broadly tested but the results obtained are regarded as controversial. In the present study, 302 glioblastoma specimens were studied to evaluate a possible association between clinical outcome and expression of some immunohistochemical variables. Furthermore, tumors examined were subdivided on the three cytological subsets--small-cell (SGB), pleomorphic-cell (PGB) and gemistocytic (GGB). Immunohistochemical variables differed between various subsets: the number of p53-positive tumors was found to be prevailed among the PGB, whereas the number of tumors with EGFR and mdm2 positivity was significantly greater in SGB. GGB contained significantly lowest mean proliferating cell nuclear antigen (PCNA) labeling index (LI), greater number of p21ras positive cases, and higher mean apoptotic index (AI). Survival time in patients with SGB, EGFR and mdm2-positivity and PCNA LI >40% was found to be significantly shorter, whereas presence of p21ras and AI >0.5% were associated with prolonged survival. Multivariate analysis revealed that survival time is associated with SGB, EGFR-positivity, and AI (p = 0.0023, p = 0.0035 and p = 0.0029 respectively). We conclude that although some immunohistochemical variables were found to be significant for glioblastoma outcome, they appear to be closely related to biology of single cytological subsets. Furthermore, these variables exhibited no prognostic value when they were analyzed within each cytological subset separately. Therefore, the glioblastoma subdivision on three cytological subsets proposed by us is carrying some element of rationality but, undoubtedly, requires further prospective studies.
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PMID:Immunohistochemical markers for prognosis of cerebral glioblastomas. 1218 57

Amplification of the EGFR, mdm2, CDK4 and PDGFR A genes has been widely demonstrated in adult malignant gliomas, almost exclusively glioblastomas. To determine the role of these mutational events in pediatric astrocytic gliomas we investigated the presence of EGFR, mdm2, CDK4 and PDGFR A gene amplification in 38 childhood brain tumor biopsies, including 24 low-grade astrocytomas and 14 malignant tumors. We used differential PCR assay on DNA extracted either from paraffin embedded or frozen tissues. EGFR gene amplification was detected in 4 out of 14 malignant tumors; no low-grade astrocytoma showed amplification. Tumors with EGFR gene amplification were negative for the presence of p53 mutations, as observed in a previous study. One glioblastoma showed PDGFR A amplification, while no amplifications were observed for mdm2 and CDK4 genes. These data are in line with those obtained from studies on gliomas of adults and suggest the existence of two different subsets of malignant gliomas also in pediatric brain tumors: one carrying EGFR gene amplification, the other showing p53 mutations.
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PMID:Molecular genetic changes in a series of neuroepithelial tumors of childhood. 1224 Nov 4

In Singapore astrocytic tumours occur in only 25% of patients with primary brain tumours compared to 40-60% in other series. Glioblastoma multiforme arises either de novo as a primary glioblastomas associated with epidermal growth factor receptor (EGFR) and mdm2 over-expression or as a secondary glioblastomas, through malignant progression from low-grade astrocytomas, associated with p53 mutations and PDGFR-alpha over-expression. Using immunohistochemical methods and DNA sequencing, we studied our population of glioblastomas for overexpression of EGFR, mdm2, p53, and PDGFR-alpha as well directly for mutations of the p53 gene. While levels of over-expression of EGFR and mdm2 were consistent with levels expected for primary glioblastomas, levels of p53 and PDGFR-alpha were consistent with levels documented for secondary glioblastomas. Notably 96% of the samples over-expressed p53 as detected with monoclonal antibody pAb 240. Of the 39 samples available for DNA sequencing 18% (7/39) had p53 mutations, including three mutations previously undocumented in glioblastomas. These results provide strong evidence that glioblastomas in Asian patients do not conform to currently accepted models of glioblastoma development, and that clinically defined glioblastomas in these patients show genetic changes consistent with both 'primary' and 'secondary' glioblastomas.
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PMID:Glioblastoma multiforme in an Asian population: evidence for a distinct genetic pathway. 1263 58

Nuclear factor-kappaB (NF-kappaB) activation may play an important role in the pathogenesis of cancer and also in resistance to treatment. Inactivation of the p53 tumor suppressor is a key component of the multistep evolution of most cancers. Links between the NF-kappaB and p53 pathways are under intense investigation. In this study, we show that the receptor interacting protein 1 (RIP1), a central component of the NF-kappaB signaling network, negatively regulates p53 tumor suppressor signaling. Loss of RIP1 from cells results in augmented induction of p53 in response to DNA damage, whereas increased RIP1 level leads to a complete shutdown of DNA damage-induced p53 induction by enhancing levels of cellular mdm2. The key signal generated by RIP1 to up-regulate mdm2 and inhibit p53 is activation of NF-kappaB. The clinical implication of this finding is shown in glioblastoma, the most common primary malignant brain tumor in adults. We show that RIP1 is commonly overexpressed in glioblastoma, but not in grades II and III glioma, and increased expression of RIP1 confers a worse prognosis in glioblastoma. Importantly, RIP1 levels correlate strongly with mdm2 levels in glioblastoma. Our results show a key interaction between the NF-kappaB and p53 pathways that may have implications for the targeted treatment of glioblastoma.
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PMID:The receptor interacting protein 1 inhibits p53 induction through NF-kappaB activation and confers a worse prognosis in glioblastoma. 1933 67


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