Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human polyomavirus, JCV, is the causative agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal human demyelinating disease. PML results from the cytolytic destruction of oligodendrocytes, the myelin-producing cells of the nervous system. JCV has also been shown to be tumorigenic in several animal models. Transgenic mice expressing the JCV early protein, T-antigen, develop poorly differentiated neural crest origin tumours. Intracerebral inoculation of JCV into newborn hamsters induces medulloblastomas, astrocytomas, and primitive neuroectodermal tumours. Further, inoculation of the virus into the brains of non-human primates, owl and squirrel monkeys, results in astrocytomas and glioblastoma multiforme. Several case reports have associated JCV with human CNS tumours in patients with concomitant PML, and one such report has detected JCV in a glial tumour in the absence of PML. The induction of neural origin tumours by JCV has been studied in transgenic mice harbouring the early genome of the virus. Alterations in the level and function of tumour suppressor proteins p53 and Rb, as well as associated cell cycle regulators, have been detected in tumour tissue from JCV T-antigen transgenic mice. Possible mechanisms by which JCV may exert its oncogenic potential by alteration of cellular growth control pathways in both humans and experimental animals are discussed.
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PMID:Oncogenic potential of human neurotropic papovavirus, JCV, in CNS. 977 30

Deregulated expression of one or more growth control genes including p16, p53, EGF receptor (EGFR), MDM2 or Bcl-2 may contribute to the treatment resistance phenotype of GBM and generally poor patient survival. Clinically, GBM have been divided into two major groups defined by (1) histologic progression from a low grade tumor ("progressive" or "secondary" GBM) contrasted with (2) those which show initial clinical presentation without a prior history ("de novo" or "primary" GBM). Using molecular genetic analysis for p53 gene mutations together with immunophenotyping for overexpression of EGFR, up to four GBM variants can be distinguished, including the p53+/EGFR- progressive or the p53-/EGFR+ de novo variant. We examined the survival of 80 adult patients diagnosed with astrocytic GBM stratified by age category (>40, 41-60 or 61-80) to determine whether alterations in any one given growth control gene or whether different genetic variants of GBM (progressive versus de novo) were associated with different survival outcomes. Survival testing using Kaplan-Meier plots for GBM patients with or without altered expression of p16, p53, EGFR, MDM2 or Bcl-2 showed no significant differences by age group or by gene expression indicating a lack of prognostic value for GBM. Also the clinical outcome among patients with GBM showed no significant differences within each age category for any GBM variant including the progressive and de novo GBM variants indicating similar biologic behavior despite different genotypes. Using a pairwise comparison, one-third of the GBM with normal p16 expression showed accumulation of MDM2 protein and this association approached statistical significance (0.01 < P < 0.05) using the Bonferroni procedure. These GBM may represent a variant in which the p19ARF/MDM2/p53 pathway may be deregulated rather than the p16/cyclin D-CDK4/Rb pathway.
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PMID:Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM2 or Bcl-2 genes. 980 75

Abnormal p53 as revealed by immunostaining has been shown to be a predictor of poor outcome in a variety of malignant tumors. This study examines the relationship of p53 immunostaining and survival in 182 adult patients with gliomas. Tumor tissues obtained from patients with glioma within 4 months of initial diagnosis were investigated by immunohistochemical analysis for detection of p53 protein abnormalities using the monoclonal antibody PAb 1801. There were 122 patients with glioblastoma multiforme, 48 patients with anaplastic glioma, and 12 patients with low-grade glioma. Among these patients, 73 of those with glioblastoma multiforme, 35 with anaplastic glioma, and 6 with low-grade glioma had positive p53 immunoreactivity. Kaplan-Meier survival plots (log rank test) showed that the patients with anaplastic astrocytoma or low-grade glioma and p53-positive tumors had longer survival times compared to the patients with p53-negative tumors. No differences in survival were detected among the glioblastoma patients. Cox proportional hazards regression analysis, adjusted for age at diagnosis, showed that the p53 positivity was a significant predictor of longer survival (relative risk = 0.56; 95% confidence intervals = 0.35, 0.90; P = 0. 015) in anaplastic astrocytoma patients, but not in glioblastoma patients (relative risk = 1.03; 95% confidence intervals = 0.82, 1. 29; P = 0.80). These results suggest that anaplastic glioma patients with p53 protein alterations may have a better response to chemoradiation, possibly because the malignant cells cannot arrest in G1 to correct lethal damage induced by chemotherapy or radiotherapy.
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PMID:Prognostic significance of p53 immunoreactivity in patients with glioma. 981 64

Gliomas were induced in adult male Sprague-Dawley rats by continuous exposure to 100 ppm of N-nitrosmethylurea (MNU) in drinking water. Latency periods for such tumors were 20 and 50 weeks following completion of exposure intervals of 20, 15, and 10 weeks, respectively. Based on histomorphology and the pattern of GFAP immunoreactivity, a large percentage of MNU-induced tumors (>40%) were anaplastic mixed gliomas, having both neoplastic astrocytic and oligodendroglial components. Typical oligodendrogliomas and astrocytomas also occurred less frequently. Unlike the majority of tumors induced by ethylnitrosourea (ENU), MNU yielded glial tumors that did not express synaptophysin. Anaplastic mixed gliomas and glioblastoma multiforme (GBMs) had no missense p53 mutations in the commonly mutated exons 4 through 8 and did not overexpress wild-type p53, suggesting that MNU-induced oncogenesis in rat brain tumors may not require inactivation/alteration of the p53 tumor suppressor gene. The K-ras gene was also analyzed and found to have no activating mutations in brain tumors. This model is suitable for studying genetic events leading to the majority of gliomas that apparently express functional p53.
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PMID:Glial tumors in the MNU rat model: induction of pure and mixed gliomas that do not require typical missense mutations of p53. 982 42

Protein kinase Calpha (PKCalpha) expression is related to tumor progression in glioblastoma multiforme (GBM), the most common malignant brain tumor in adults. To determine whether PKCalpha regulates an anti-apoptotic survival pathway in GBM, A172 GBM cells were treated with a PKCalpha-selective antisense oligonucleotide. PKCalpha antisense oligonucleotide treatment was accompanied by reduction in PKCalpha levels and the induction of wild-type p53 and insulin-like growth factor-binding protein-3 (IGFBP3) 24-72 h after treatment, a period that coincided with the appearance of apoptotic cell death as detected by DNA fragmentation. There were no significant changes in the levels of Bcl-XL, Bax, and p21(WAF1). Induction of p53 after PKCalpha down-regulation was not associated with increased mRNA expression, but increased IGFBP3 levels were accompanied by increased mRNA levels. Recombinant human IGFBP3 induced an apoptotic effect that was similar to the PKCalpha antisense oligonucleotide, and its effect was blocked by IGF-I. These results suggest that one mechanism by which PKCalpha produces its antiapoptotic activity in GBM cells is by suppressing the p53-mediated activation of IGFBP3.
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PMID:Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Calpha antisense oligonucleotide. 992 33

Angiogenesis is a prerequisite for solid tumor growth. Glioblastoma multiforme, the most common malignant brain tumor, is characterized by extensive vascular proliferation. We previously showed that transgenic mice expressing a GFAP-v-src fusion gene in astrocytes develop low-grade astrocytomas that progressively evolve into hypervascularized glioblastomas. Here, we examined whether tumor progression triggers angiogenetic signals. We found abundant transcription of vascular endothelial growth factor (VEGF) in neoplastic astrocytes at surprisingly early stages of tumorigenesis. VEGF and v-src expression patterns were not identical, suggesting that VEGF activation was not only dependent on v-src. Late-stage gliomas showed perinecrotic VEGF up-regulation similarly to human glioblastoma. Expression patterns of the endothelial angiogenic receptors flt-1, flk-1, tie-1, and tie-2 were similar to those described in human gliomas, but flt-1 was expressed also in neoplastic astrocytes, suggesting an autocrine role in tumor growth. In crossbreeding experiments, hemizygous ablation of the tumor suppressor genes Rb and p53 had no significant effect on the expression of VEGF, flt-1, flk-1, tie-1, and tie-2. Therefore, expression of angiogenic signals is an early event during progression of GFAP-v-src tumors and precedes hypervascularization. Given the close similarities in the progression pattern between GFAP-v-src and human gliomas, the present results suggest that these mice may provide a useful tool for antiangiogenic therapy research.
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PMID:Early induction of angiogenetic signals in gliomas of GFAP-v-src transgenic mice. 1002 15

Glioblastoma multiforme (GBM) often displays morphological heterogeneity in that low-grade (LG) area with well-differentiated cells are commonly found adjacent to high-grade (HG) area with poorly-differentiated cells. This heterogeneity may cause difficulty in obtaining representative tumor samples. Nevertheless, the genetic composition of these cells has only been occasionally examined. In the present study, we examined 29 de novo glioblastomas in which distinct LG and HG areas of sufficient volumes could be identified. These areas were microdissected from paraffin-embedded tissues and analyzed for genetic alterations: p53 mutations and immunohistochemistry; allelic losses at 17p13.1, 9p21, and 10q23-25; and amplification of the epidermal growth factor receptor (EGFR) gene and immunohistochemistry. We also examined 14 paired astrocytic tumors, in which a primary Grade II astrocytoma progressed over a period of time to a Grade III or Grade IV tumor. Our findings showed that the LG areas of the de novo glioblastomas exhibited numerous genetic aberrations, the proportion of which was increased in the HG areas. Genetic abnormalities seen in the LG areas were conserved in the HG areas suggesting that these morphologically different cellular subsets were derived from a common transformed clone. Also, the LG areas were genetically different from Grade II astrocytomas of the paired tumor group, in spite of their morphological similarity. In particular, the LG areas had more deletions on 10q23-25 (75% vs 20%, p = 0.04), but fewer p53 mutations (24% vs 71%, p = 0.003) and less p53 protein labeling (45% vs 79%, p = 0.04). These differences suggest that LG and HG areas in de novo glioblastoma are genetically closer to each other compared with paired low- and high-grade tumors that have progressed over time. Moreover, only a small proportion (17%) of our de novo glioblastomas exhibited EGFR amplification while a high proportion (62%) showed either p53 mutations or allelic loss of 17p13.1. We speculate that some de novo GBMs with copious LG areas may constitute a separate group with rapid progression from Grade II astrocytomas.
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PMID:Molecular analysis of microdissected de novo glioblastomas and paired astrocytic tumors. 1002 95

A puzzling finding in various human tumors, including glioblastoma multiforme (GBM), is the stabilization of wild-type (wt) p53 protein. The biological significance of this phenomenon and the mechanism by which it occurs are unexplained. Recent reports have revealed that mdm2 exerts its negative regulation on the p53 signal by directly binding p53 protein and thereby instigating its proteasomal degradation. mdm2 has been shown to exist in alternatively spliced forms in human ovarian and bladder carcinomas, and recently in GBM, with loss or disruption of its p53 binding domain. Here we report that alternatively spliced transcripts of mdm2 are present in 7 of 16 human GBM primary cell cultures and in the established GBM cell lines LN 229 and LN 18. Sequencing demonstrated loss of the amino terminal p53 binding domain in these alternatively spliced mdm2 transcripts, and an out-of-frame splicing in the majority of cases. A significant correlation between the presence of mdm2 splice variants and increased expression of wt p53 protein was observed. Furthermore, in the presence of an mdm2 splice variant, wt p53 stabilization occurred despite coincident MDM2 amplification. Our findings suggest that wt p53 protein stabilization may arise as a consequence of alternative splicing of mdm2. Such a mechanism might account for wt p53 protein accumulation in GBM cells, even in the presence of MDM2 gene amplification.
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PMID:Expression of alternatively spliced mdm2 transcripts correlates with stabilized wild-type p53 protein in human glioblastoma cells. 1007 28

Radiation-induced apoptosis can be mediated through pathways initiated by either DNA damage or ceramide-induced Fas signaling. Glioblastoma multiforme is a primary brain tumor that is highly resistant to irradiation, and U-87 MG, SF126, and T98G are glioblastoma-derived cell lines that mimic this characteristic. We found that these radioresistant glioma cells are susceptible to Fas-mediated cell death induced by treatment with either anti-Fas antibody or exogenous ceramide. Fas-mediated cell death in these cell lines is p53-independent. These data demonstrate that apoptosis can be induced by ceramide and mediated through the Fas pathway in glioma cells, although high-dose ionizing radiation fails to trigger this pathway.
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PMID:Fas (APO-1/CD95) signaling pathway is intact in radioresistant human glioma cells. 1009 71

Malignant gliomas of astrocytic origin are good candidates for gene therapy because they have proven incurable with conventional treatments. Although mutation or inactivation of the p53 tumor suppressor gene occurs at early stages in gliomas and is associated with tumor progression, many tumors including high-grade glioblastoma multiforme carry a functionally intact p53 gene. To evaluate the effectiveness of p53-based therapy in glioma cells that contain endogenous wild-type p53, a clinically relevant model of malignant human glioma was established in athymic nu/nu mice. Intracerebral, rapidly growing tumors were produced by stereotactic injection of the human U87 MG glioma cell line that had been genetically modified for tracking purposes to express the Escherichia coli lacZ gene encoding beta-galactosidase. Overexpression of the p53 gene by adenovirus-mediated delivery into the tumor mass resulted in rapid cell death with the eradication of beta-galactosidase-expressing glioma cells through apoptosis. In long-term experiments, the survival of mice treated with the p53 adenoviral recombinant was significantly longer than that of mice that had received control adenoviral recombinant. During the observation period of 1 year, a complete cure was achieved in 27% of animals after a single injection of p53 adenoviral recombinant, and 38% of the animals were tumor free in the group receiving multiple injections of p53 adenoviral recombinant into a larger tumor mass. These experiments demonstrate that overexpression of p53 in gliomas, even in the presence of endogenous functional wildtype p53, leads to efficient elimination of tumor cells. These results point to the potential therapeutic usefulness of this approach for all astrocytic brain tumors.
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PMID:Intracerebral adenovirus-mediated p53 tumor suppressor gene therapy for experimental human glioma. 1010 Jul 17


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