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)

The cellular content of mutant p53 and hsp72 proteins following gamma-ray irradiation, UV irradiation, and heat treatment was studied in A-7 cells, a human glioblastoma cell line. A-7 was found to contain a mutant p53 gene in which the arginine codon at position 175 was substituted by a histidine codon. Although the p53 gene was mutant, the phenotype of the p53 protein appeared wild-type since the cellular content of the p53 protein was limited under normal culturing conditions. The quantity of mutant p53 and hsp72 proteins in A-7 was increased by heat treatment as well as gamma-ray and UV irradiation. Furthermore, the mutant p53 protein was coimmunoprecipitated with anti-hsp72/hsc73 antibody. Additionally, hsp72 and hsc73 were coimmunoprecipitated with anti-p53 antibody. These results suggest that in A-7, p53 protein accumulation may be caused as a result of response to stressors, such as gamma-ray, UV and heat and that mutant p53 protein and hsp72/hsc73 may manage biological functions cooperatively after gamma-ray, UV and also heat treatments.
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PMID:Accumulation of mutant p53 and hsp72 by heat treatment, and their association in a human glioblastoma cell line. 759 17

We have investigated the increased levels of p53 and hsp72 after UV or gamma-ray irradiation and the association of these using two human glioblastoma cell lines. Human glioblastoma cell line A-172 exhibited no mutations in the p53 gene, whereas cell line T98G had a mutation in exon 7 of the p53 gene. In A-172, the level of wild-type p53 was increased by UV or gamma-ray irradiation. Although the level of mutant p53 in T98G was very high before irradiation, it was unchanged by UV or gamma-ray irradiation. Furthermore, in the A-172 cell line after UV or gamma-ray irradiation, wild-type p53 was co-immunoprecipitated with anti-hsp72/73 antibody, and accumulated hsp72 was also co-immunoprecipitated with anti-p53 antibody. These findings indicate that wild-type p53 accumulated by UV or gamma-ray irradiation is associated with hsp72 induced by these treatments.
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PMID:Binding between wild-type p53 and hsp72 accumulated after UV and gamma-ray irradiation. 760 May 22

The sensitivity of polymerase chain reaction (PCR)-based methods for the detection of DNA offers opportunities for tumor diagnosis from the small amounts of tumor-derived DNA released into body fluids. Tumor-derived DNA can be distinguished from DNA derived from non-neoplastic cells by the presence of tumor specific genomic alterations, such as mutations in the p53 gene. This case report describes the use of allele-specific PCR (A-PCR) to detect a C-->T transition in p53 codon 273 in DNA extracted from the cerebrospinal fluid (CSF) of a patient whose glioblastoma contained the same mutation. The results of this study were confirmed by a second independent A-PCR reaction that detected the corresponding G-->A transition on the opposite strand. The specificity of the A-PCR protocol was demonstrated by negative controls, including pooled human placental DNA and the patient's non-tumor DNA, and by the use of A-PCR primers to detect all four possible bases at the site of the mutation. The methodology used in this study is suitable for use as a diagnostic clinical test. Because about half of all human tumors contain p53 mutations, PCR examination of CSF for the presence of mutant p53 sequences may be useful in the diagnosis of recurrent or metastatic tumors. Patients with known carcinoma of the breast or lung might be particularly benefited by this test.
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PMID:PCR-detection of tumor-derived p53 DNA in cerebrospinal fluid. 772 35

Mutation of the p53 tumor suppressor gene is one of the earliest identified genetic lesions during malignant progression of human astrocytomas. To assess the functional significance of these mutations, wild-type (WT) p53 genes were introduced into glioblastoma cell lines having mutant, WT, or null endogenous p53 alleles. Populations of cells with mutant or null endogenous p53 alleles and exogenous WT p53 were spontaneously selected in culture for cells expressing only mutant p53 or no p53, which then displayed a growth and tumorigenic phenotype identical to the parental cells. To determine the phenotypic consequences of WT p53 expression before the occurrence of mutations, we developed a single cell assay to monitor WT p53-dependent transcription activity. Transfer and expression of exogenous WT p53 genes to cells with endogenous mutant or deleted, but not WT, p53 alleles caused growth arrest and morphological changes, including increased cell size and acquisition of multiple nuclei. This supports the hypothesis that genetic lesions of the p53 gene play an important role in the genesis of astrocytomas. Furthermore, the high sensitivity of the episomal single cell reporter strategy developed here has potential clinical applications in the rapid screening of patients for germ-line mutations of the p53 gene or any other gene with known targets for transcriptional transactivation.
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PMID:Single cell monitoring of growth arrest and morphological changes induced by transfer of wild-type p53 alleles to glioblastoma cells. 786 24

We investigated the accumulation of p53 proteins after heat stress and their association with HSP72/HSC73 using four human glioblastoma cell lines. Human glioblastoma cell lines U-87MG and A-172 exhibited no mutation in the region between the 2nd and 11th exons of the p53 gene, whereas A-7 and T98G had mutations in exon 5 and exon 7 of the p53 gene, respectively. In U-87MG and A-172, the levels of wild-type p53 protein were slightly increased by heat stress. Levels of mutant p53 protein were apparently increased by heat stress in A-7, but not in T98G. Furthermore, wild-type p53 proteins in both U-87MG and A-172 co-immunoprecipitated with anti-HSP72/HSC73 antibody and HSP72 and HSC73 in them co-immunoprecipitated with anti-p53 antibody as did the mutant p53 proteins. These findings suggest that p53 proteins accumulated by heat stress are associated with HSP72 and HSC73.
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PMID:p53 proteins accumulated by heat stress associate with heat shock proteins HSP72/HSC73 in human glioblastoma cell lines. 795 68

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 product of the p53 gene suppresses cell growth and plays a critical role in suppressing development of human tumors. p53 protein binds DNA, activates transcription, and can be phosphorylated at N- and C-terminal sites. Previously, wild-type p53 was shown to be hyperphosphorylated compared to mutant p53 during p53-mediated growth arrest in vivo. Here we show that Ser-15 and Ser-9 in the N-terminal transactivation domain of wild-type human p53 are phosphorylated in vivo in cells derived from the human glioblastoma line T98G. In [Ile237]p53 and [Ala143]p53, two natural p53 mutants from human tumors that are defective for activation of transcription, phosphorylation at Ser-15 was reduced and phosphorylation at Ser-392 was increased compared to wild-type p53. No change was observed at Ser-9. [His273]p53, a third mutant, had a phosphorylation state similar to that of wild-type p53. We suggest that phosphorylation of Ser-15 may depend on the ability of p53 to adopt a wild-type conformation and may contribute to p53's ability to block cell growth.
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PMID:Phosphorylation at Ser-15 and Ser-392 in mutant p53 molecules from human tumors is altered compared to wild-type p53. 832 66

It is known that transfer of the wild-type p53 gene into p53-negative cells from transgenic mice increases their sensitivity to drug and radiation-induced apoptosis. However, unlike many human tumors, these transgenic cells do not express mutant p53, and it is not known from these earlier studies whether wild-type p53 dominates the effects of mutant p53 with respect to drug and radiation sensitivity. We addressed this question in glioblastoma, a disease characterized by an unusually high level of intrinsic resistance to therapy and poor prognosis: mean survival time from diagnosis is only about 1 yr. We introduced the gene for wild-type p53 into human T98G glioblastoma cells, which express endogenous mutant p53 but not wild-type p53. Stable transfectants that co-expressed mutant and wild-type p53 had enhanced sensitivity to cisplatin and gamma radiation, compared with parental cells, control vector-transduced cells, and transduced cells that had lost expression of wild-type p53. Transient wild-type p53 expression after high-efficiency gene transfer by a p53 adenovirus also sensitized the cells to cisplatin and correlated with the induction of apoptosis. The sensitization effect was also observed in p53 adenovirus-infected H23 small cell lung carcinoma cells, which express endogenous mutant p53. Therefore, wild-type p53 gene transfer has dominant effects over mutant p53 in sensitizing tumor cells to therapy, which supports the potential of p53 gene therapy to enhance the efficacy of traditional therapy.
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PMID:Use of wild-type p53 to achieve complete treatment sensitization of tumor cells expressing endogenous mutant p53. 851 17

The WAF1/Cip1 protein is an important regulator at the G1 checkpoint in the cell cycle. The WAF1/Cip1 protein binds to the cyclin-dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. We investigated the expression of WAF1/Cip1 protein in 14 glioblastoma cell lines and found that WAF1/Cip1 expression was detectable in many of the cell lines, even when mutant p53 was present. We also showed that WAF1/Cip1 protein level was very low in LN-Z308 cells that do not express endogenous p53. Transfection of the wild-type p53 into this cell line activated WAF1/Cip1 expression and inhibited cell growth. In contrast, transfection of the p53 mutant 248Trp failed to activate WAF1/Cip1 expression. Transfection of WAF1/Cip1 alone also inhibited LN-Z308 cell proliferation. However, cotransfection of the p53 mutant 248Trp with WAF1/Cip1 attenuated the growth-suppression effect of WAF1/Cip1. Our analysis with Western blot showed that the levels of cyclin E increased in cells transfected with p53 mutants. We conclude that p53 mutants may counter the negative regulators, such as WAF1/Cip1, by the elevation of positive cell cycle regulators, and the presence of WAF1/Cip1 in tumor cells is not sufficient for growth inhibition.
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PMID:Inhibition of human glioblastoma cell growth by WAF1/Cip1 can be attenuated by mutant p53. 854 19

Induction of WAF1 expression was investigated after heat treatment (44 degrees C, 30 min) in two human glioblastoma cell lines with the wild-type or a mutant p53 gene. WAF1 accumulation was induced by heat treatment in A-172 cells carrying the wild-type p53 gene but not in T98G cells carrying the mutant p53 gene. We examined whether this phenomenon was due to the induction of WAF1 expression. Northern blot analysis showed that heat treatment not only activated WAF1 but also up-regulated p53 expression only in A-172 cells carrying the wild-type p53 gene. Gel mobility shift assay indicated an increase in p53 DNA binding activity after heat treatment. These findings suggest that the WAF1 expression is heat-inducible in human glioblastoma cells and that this induction may be due to signal transduction mediated by p53 in response to heat stress.
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PMID:p53-dependent induction of WAF1 by heat treatment in human glioblastoma cells. 866 96


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