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)

Loss of function of the p53 tumor suppressor gene due to mutation occurs early in astrocytoma tumorigenesis in about 30-40% of cases. This is believed to confer a growth advantage to the cells, allowing them to clonally expand due to loss of the p53-controlled G1 checkpoint and apoptosis. Genetic instability due to the impaired ability of p53 to mediate DNA damage repair further facilitates the acquisition of new genetic abnormalities, leading to malignant progression of an astrocytoma into anaplastic astrocytoma. This is reflected by a high rate of p53 mutation (60-70%) in anaplastic astrocytomas. The cell cycle control gets further compromised in astrocytoma by alterations in one of the G1/S transition control genes, either loss of the p16/CDKN2 or RB genes or amplification of the cyclin D gene. The final progression process leading to glioblastoma multiforme seems to need additional genetic abnormalities in the long arm of chromosome 10; one of which is deletion and/or functional loss of the PTEN/MMAC1 gene. Glioblastomas also occur as primary (de novo) lesions in patients of older age, without p53 gene loss but with amplification of the epidermal growth factor receptor (EGFR) genes. In contrast to the secondary glioblastomas that evolve from astrocytoma cells with p53 mutations in younger patients, primary glioblastomas seem to be resistant to radiation therapy and thus show a poorer prognosis. The evaluation and design of therapeutic modalities aimed at preventing malignant progression of astrocytomas and glioblastomas should now be based on stratifying patients with astrocytic tumors according to their genetic diagnosis.
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PMID:Roles of the functional loss of p53 and other genes in astrocytoma tumorigenesis and progression. 1155 Mar 8

Human malignant gliomas are thought to develop as the result of stepwise accumulations of multiple genetic alterations. Recently, we showed that E6/E7-mediated inactivation of p53/pRb, ras pathway activation (initiated by expression of mutant H-Ras), and expression of human telomerase reverse transcriptase (hTERT) in combination converted normal human astrocytes into cells that formed intracranial tumors resembling human anaplastic astrocytoma (AA). In this study, we created human astrocytes that, in addition to expressing E6/E7, hTERT, and Ras, also expressed a constitutive activated form of Akt intended to mimic the Akt activation noted in grade IV glioblastoma multiforme (GBM). Although these cells grew no differently than astrocytes expressing E6, E7, and H-Ras in vitro or in the first 28 days following s.c. implantation, they ultimately formed tumors four to six times larger than those formed by the E6/E7/hTERT/Ras cells. Unlike the poorly vascularized, necrosis-free AA formed by E6/E7/hTERT/Ras cells, the tumors formed by s.c. or intracranial injection of Akt-expressing cells had large areas of necrosis surrounded by neovascularization and were consistent in appearance with grade IV human GBM. These results show that activation of the Akt pathway is sufficient to allow conversion of human AA to human GBM.
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PMID:Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. 1155 33

Malignant astrocytoma is one of the most deadly primary central nervous system tumors. Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively little analysis has been done in childhood astrocytomas, which are less common and have a more favorable prognosis. Our previous studies of an institutional cohort of children with malignant gliomas suggested the existence of distinct molecular pathways of tumorigenesis in younger versus older children, based on the finding of a high frequency of TP53 mutations in tumors from children >3 years of age at diagnosis, compared with those from younger children. In the current study, the association between TP53 mutations and age was examined in greater detail using the multi-institutional group of children enrolled in Children's Cancer Group Study 945, the largest cohort of childhood high-grade gliomas analyzed to date. Seventy-seven tumors with centrally reviewed diagnoses of anaplastic astrocytoma or glioblastoma multiforme had sufficient archival histopathological material for microdissection-based genotyping. Sections were examined histologically, and topographic targets that contained malignant tissue were isolated by microdissection and subjected to PCR-based amplification and sequencing of TP53 exons 5-8. Twenty-six tumors (33.8%) had mutations in those exons. Mutations were observed in 2 of 17 tumors (11.8%) from children <3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children, a difference that was statistically significant (P = 0.04), in agreement with our previous results. Whereas malignant gliomas in older children have a frequency of mutations comparable to tumors that arise in young adults, those from children <3 years old do not. The association between age and frequency of TP53 mutations among pediatric malignant gliomas indicates the probable existence of two distinct pathways of molecular tumorigenesis in younger versus older children.
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PMID:Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort. 1160 70

Despite many efforts to alter the relentlessly aggressive progression of tumors of neural origin, individuals bearing these tumors exhibit poor prognosis for long-term survival. In an attempt to find an effective treatment, we examined the efficacy of the non-steroidal anti-inflammatory drug, flurbiprofen, to suppress the growth of tumor cell lines derived from medulloblastoma and glioblastoma multiforme. Results from cell proliferation assays have revealed that flurbiprofen effectively inhibits the growth of various tumor cells in a dose-dependent manner and causes a noticeable change in the progression of cells through cell cycle stages. Treatment of tumor cells with flurbiprofen reduced the number of cells in G1 and G2, and significantly increased their numbers in S phase, suggesting that, flurbiprofen accelerates G1/S entry, and/or delays cell exit from S to G2/M stages. Results from RNase protection assay and Western blot analysis showed that while treatment of cells with flurbiprofen causes a minor change in the RNA level of different cyclins, there is a significant decrease in the level of cyclin B protein upon flurbiprofen treatment. Examination of tumor suppressors by RNase protection technique showed a subtle increase in the levels of several tumor suppressors upon flurbiprofen treatment. Interestingly, at the protein level, p53 tumor suppressor was substantially increased upon flurbiprofen treatment, yet the level of p21, a downstream target for p53 remained unchanged. Curiously, treatment of the cells with flurbiprofen enhanced the level of COX-2 expression. Results from co-immunoprecipitation showed association of COX-2 with p53 in tumor cells. These observations suggest that the interaction of COX-2 with p53 may cause p21-independent suppression of tumor cell growth upon flurbiprofen treatment.
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PMID:Inhibition of human brain tumor cell growth by the anti-inflammatory drug, flurbiprofen. 1168 65

Infiltrative astrocytic neoplasms are the most common malignancies of the central nervous system. They remain clinically problematic because of their involvement of brain structures critical to proper cognitive, behavioral, and motor function; their widely invasive properties, which make them difficult to resect totally; and their nearly inevitable biologic progression in spite of adjuvant therapy. Glioblastoma multiforme (GBM, World Health Organization grade IV), the most malignant form of infiltrating astrocytoma, can present as a high-grade lesion from the outset (so-called de novo GBM) or can evolve from a lower grade precursor lesion (secondary GBM). Molecular genetic investigations suggest that GBM is best regarded as a clinicopathologic entity composed of multiple molecular genetic subsets. Molecular alterations associated with progression to GBM and that define genetic subsets include epidermal growth factor receptor amplifications, p53 mutations, retinoblastoma pathway alterations [most commonly, p16(CDKN2A) losses], and chromosome 10 alterations, including PTEN mutations. Despite the wide range of genetic events that ultimately lead to GBM, the vascular changes that evolve are remarkably similar. Microvascular hyperplasia is spatially and temporally associated with pseudopalisading necrosis in GBM and is believed to be driven by hypoxia-induced expression of proangiogenic cytokines such vascular endothelial growth factor. In addition, genetic alterations in GBM are thought to contribute directly or indirectly to angiogenic dysregulation. Both p53 mutations and genetic losses on chromosome 10 may tip the balance toward an angiogenic phenotype through upregulation of proangiogenic factors and/or downregulation of angiogenesis inhibitors. Understanding genetic events and their relation to angiogenic regulation in astrocytic neoplasms may eventually lead to therapies that are specifically directed at molecularly defined subsets of these diseases.
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PMID:Genetic and biologic progression in astrocytomas and their relation to angiogenic dysregulation. 1175 57

Gliomatosis cerebri (GC) is a rare tumor of the central nervous system (CNS) characterized by widespread diffuse infiltration of the brain and spinal cord by neoplastic glial cells. We report the case of a 17-year-old boy with a bioptically diagnosed fibrillary astrocytoma. The administration of thalidomide, which was suggested to be beneficial in the treatment of human cancers, had no substantial clinical effect on our patient. Autopsy studies revealed a diffuse infiltration of the frontal and temporal lobes of the right hemisphere, brainstem, and the leptomeninges covering the whole spinal cord by an astrocytic tumor, which showed features both of low-grade astrocytoma and glioblastoma multiforme. No mutations in the p53 and PTEN tumor suppressor genes were found; immunoreactivities for p53, PTEN, and EGFR could not be detected.
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PMID:Gliomatosis cerebri: post-mortem molecular and immunohistochemical analyses in a case treated with thalidomide. 1180 78

Intrinsic chemoresistance constitutes a major problem in the therapy of malignant gliomas. In vitro experiments with four astrocytoma/glioblastoma (AC/GBM) cell lines revealed that the chemoresistance of two cell lines, A172 and T98G, to cisplatin and etoposide was due to resistance to drug-induced apoptosis. In contrast, all the AC/GBM cell lines tested were sensitive to treatment with the lipophilic ether lipid erucylphosphocholine, ErPC. ErPC-induced apoptosis was independent of wild-type p53-signaling and triggering of the CD95/CD95 ligand (CD95L) system. Inhibition of protein and RNA synthesis by cycloheximide and actinomycin D did not abrogate ErPC-induced apoptosis. However, expression of members of the bcl-2 protein family was modulated during ErPC treatment. Activation of caspase 3 and mitochondrial alterations were central to ErPC-induced apoptosis. We conclude that ErPC-induced activation of the mitochondrial pathway enables cell death in the chemoresistant AC/GBM cells.
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PMID:Erucylphosphocholine-induced apoptosis in chemoresistant glioblastoma cell lines: involvement of caspase activation and mitochondrial alterations. 1184 99

Although several studies have examined brain tumor markers for prognostic value, few investigations have stratified analysis based on specific histologic grade. The objective of this study was to evaluate a single histologic grade of glioma, the grade IV glioma or glioblastoma (World Health Organization Classification), with a comprehensive panel of tumor markers in an attempt to identify those with prognostic significance. Tumor samples from a cohort of patients with glioblastoma multiforme (n = 32) were examined for tumor markers, DNA analysis, and clinical variables in an attempt to determine a 'profile' for this tumor. We used univariate and multivariate statistical analysis to determine the prognostic value of tumor cell ploidy, percent S-phase, DNA index, p53, and Ki-67 labeling index, as well as the variables of gender, race, age, location of tumor, history of chemotherapy, and primary versus recurrent tumor. Two additional tumor markers, multidrug resistance gene 1 and glutathione-S-transferase subtype pi, were included in the sample testing, but were not analyzed statistically. Univariate analysis indicated that increasing age had a strong association with decreased survival. Female gender, increasing Ki-67, no chemotherapy before sample collection, and primary glioblastoma showed some association with decreased survival in the univariate model. The univariate results indicated that race, side of tumor, ploidy, S-phase, DNA index, and p53 had no prognostic value. Multivariate modeling demonstrated that age, gender, and Ki-67 were the strongest factors associated with survival. The relevant literature is reviewed.
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PMID:The prognostic value of tumor markers in patients with glioblastoma multiforme: analysis of 32 patients and review of the literature. 1185 75

Tumors of glial origin such as glioblastoma multiforme (GBM) comprise the majority of human brain tumors. Patients with GBM have a very poor survival rate, with an average life expectancy of <1 year. We asked whether we could identify a survival pathway in high-grade glioma and oligodendroglioma cells that when suppressed, would induce apoptosis of these tumor cells but not of normal human adult astrocytes. To identify these pathways, we selectively suppressed the activity of a number of proteins (Ras, Rac1, Akt1, RhoA, c-jun, and MEK1/2) hypothesized to play roles in cell survival. We found that suppression of Rac1, a small GTP-binding protein, inhibited survival and produced apoptosis in three human glioma cell lines (U87, U343, and U373). Serum induced the activity of Rac1 and the activity or phosphorylation state of p21-activated kinase 1 and c-Jun NH(2)-terminal kinase (JNK), two intracellular targets of Rac1. Suppression of Rac1 also induced apoptosis in 19 of 21 short-term cultures of human primary cells from grades II and III oligodendroglioma and grade IV glioblastoma that varied in p53, epidermal growth factor receptor, epidermal growth factor receptor vIII, MDM2, and p16/p19 mutational or amplification status. In contrast, inhibition of Rac1 activity did not induce apoptosis of normal primary human adult astrocytes. In both established glioma cell lines and primary glioma cells, apoptosis induced by the inhibition of Rac was partially rescued by activated mitogen-activated protein kinase kinase 1, an activator of JNK, suggesting that JNK functions downstream of Rac1 in glioma cells. These results indicate that Rac1 regulates a major survival pathway in most glioma cells, and that suppression of Rac1 activity stimulates the death of virtually all glioma cells, regardless of their mutational status. Agents that suppress Rac1 activity may therefore be useful therapeutic treatments for malignant gliomas.
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PMID:Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. 1192 35

BACKGROUND: The p16INK4A gene product halts cell proliferation by preventing phosphorylation of the Rb protein. The p16INK4a gene is often deleted in human glioblastoma multiforme, contributing to unchecked Rb phosphorylation and rapid cell division. We show here that transduction of the human p16INK4a cDNA using the pCL retroviral system is an efficient means of stopping the proliferation of the rat-derrived glioma cell line, C6, both in tissue culture and in an animal model. C6 cells were transduced with pCL retrovirus encoding the p16INK4a, p53, or Rb genes. These cells were analyzed by a colony formation assay. Expression of p16INK4a was confirmed by immunohistochemistry and Western blot analysis. The altered morphology of the p16-expressing cells was further characterized by the senescence-associated beta-galactosidase assay. C6 cells infected ex vivo were implanted by stereotaxic injection in order to assess tumor formation. RESULTS: The p16INK4a gene arrested C6 cells more efficiently than either p53 or Rb. Continued studies with the p16INK4a gene revealed that a large portion of infected cells expressed the p16INK4a protein and the morphology of these cells was altered. The enlarged, flat, and bi-polar shape indicated a senescence-like state, confirmed by the senescence-associated beta-galactosidase assay. The animal model revealed that cells infected with the pCLp16 virus did not form tumors. CONCLUSION: Our results show that retrovirus mediated transfer of p16INK4a halts glioma formation in a rat model. These results corroborate the idea that retrovirus-mediated transfer of the p16INK4a gene may be an effective means to arrest human glioma and glioblastoma.
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PMID:Retroviral transfer of the p16INK4a cDNA inhibits C6 glioma formation in Wistar rats. 1198 28


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