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)

Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such "glioblastomas with oligodendroglial component", we investigated 13 of these tumors for genetic alterations and/or expression of the TP53, CDKN2A, PTEN, and EGFR genes. In addition, we performed microsatellite analyses for loss of heterozygosity (LOH) on chromosome arms 1p, 19q and 10q. None of tumors showed evidence for LOH on 10q. LOH on 1p was detected in 3 tumors, 1 of which additionally showed LOH on 19q. The 3 tumors with LOH on 1p showed neither TP53 mutations nor nuclear p53 accumulation. In contrast, 9 of 10 tumors without demonstrated losses on 1p showed nuclear p53 accumulation. TP53 mutations were identified in 3 of these cases. Further aberrations detected were epidermal growth factor receptor (EGFR) overexpression (3 of 13 tumors), homozygous CDKN2A deletion (2 of 11 tumors), and PTEN mutation (1 of 13 tumors). Taken together, our results indicate that "glioblastomas with oligodendroglial component" carry heterogeneous genetic alterations. LOH on 10q, PTEN mutation, and homozygous CDKN2A deletion appear to be less common in these tumors as compared to ordinary glioblastomas. Furthermore, a subset of these tumors demonstrates LOH on 1p, i.e., an alteration that has recently been linked to chemosensitivity and good prognosis in anaplastic oligodendrogliomas.
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PMID:Molecular genetic alterations in glioblastomas with oligodendroglial component. 1135 2

Classification of gliomas according to their molecular characteristics may be important in future histopathological diagnosis. However, gliomas frequently display heterogeneity at the histological, biological and molecular level. In this study of archival diagnostic gliomas, precision microdissection was used to enrich samples in the most malignant cells or to investigate intratumoural histological heterogeneity. Analysis of tumour samples microdissected from the most aggressive regions, representative of the histopathological diagnosis, revealed PTEN mutations in 4/14 anaplastic astrocytomas, 4/13 glioblastomas and 1 gliosarcoma, but not in 19 low-grade gliomas. Using a novel PCR procedure and direct sequence analysis of the entire coding sequence, TP53 mutations were detected in 1/3 pilocytic astrocytomas, 3/13 astrocytomas, 4/14 anaplastic astrocytomas, 5/13 glioblastomas and 1 gliosarcoma. All but one of the tumours with TP53 mutation showed p53 immunopositivity, but 5 low-grade and 10 high-grade gliomas had p53 protein nuclear accumulation in the absence of detectable mutation. p53 status was unrelated to p21 expression. Neither PTEN nor TP53 mutations influenced the proliferative index or microvessel density of high-grade astrocytomas. Unusual findings include: TP53 mutation in a juvenile pilocytic astrocytoma; TP53 and PTEN mutations in a de novo glioblastoma, a gliosarcoma with identical mutations in gliomatous and sarcomatous components, and an infratentorial anaplastic astrocytoma with an earlier supratentorial grade II astrocytoma bearing the same TP53 mutation but not the PTEN mutation or loss of heterozygosity (LOH) of 10q23. Similarly, the transition to high-grade histology was associated with acquisition of PTEN mutations and 10q23.3 LOH in two de novo high-grade tumours with regions of low-grade histology.
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PMID:Characterisation of molecular alterations in microdissected archival gliomas. 1135 3

Current therapies for glioblastoma multiforme are ineffective. Therefore, novel therapies that target specific differences between normal and malignant cells are urgently needed. Abnormalities of cell-cycle related genes are a common feature of cancer in general and astrocytic tumors in particular. The role of these proteins is to help to regulate cell proliferation, differentiation and apoptosis. Restoring wild-type activity of critical regulators of the cell cycle to astrocytic tumors generally results in modification of the growth properties, and often the viability, of the cancer cells. Transfer of p53 induces growth arrest and, more importantly, apoptosis. Restoration of the Rb pathway results in either reversible growth arrest or senescence. Expression of E2F-1 induces transient increase of proliferation followed by massive apoptosis. Overexpression of MMAC/PTEN arrests cell cycle progression in G1 and promotes anoikis. Current knowledge of the functions of these cell-cycle controllers can be used to design small peptides and drugs to induce cell-cycle related anti-cancer effect. Inactivation of the p53 and Rb pathways in cancer cells is also being used to engineer mutant viruses that are able to replicate exclusively in cancer cells.
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PMID:Delivery of cell cycle genes to block astrocytoma growth. 1140 98

Four different genetic abnormalities may occur in endometrioid adenocarcinomas of the endometrium (mircosatellite instability and mutations in the PTEN, k-RAS and beta-catenin genes), whereas nonendometrioid carcinomas of the endometrium often have p53 mutations and loss of heterozygosity on several chromosomes. Occasionally, a nonendometrioid carcinoma may develop as a result of dedifferentiation of a preexisting endometrioid carcinoma; in such a case, the tumor exhibits overlapping clinical, morphologic, immunohistochemical, and molecular features of the 2 types. The insaturation of microsatellite instability in endometrial carcinogenesis seems to occur late in the transition from complex hyperplasia to carcinoma, and it is preceded by progressive inactivation of MLH-1 by promoter hypermethylation. Moreover, the endometrioid adenocarcinomas that exhibit microsatellite instability show a stepwise progressive accumulation of secondary mutations in oncogenes and tumor suppressor genes that contain short-tandem repeats in their coding sequences. Mutations in the PTEN and k-RAS genes are also frequent in endometrioid adenocarcinomas of the endometrium, particularly in the tumors that exhibit microsatellite instability, whereas beta-catenin mutations do not seem to be associated with such a phenomenon.
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PMID:Molecular pathology of endometrial hyperplasia and carcinoma. 1267 70

Increased expression of focal adhesion kinase (FAK) was consistently observed in low- and high-grade astrocytomas and during glioblastoma progression after radiotherapy, but not in the more benign oligodendroglioma. In glioblastoma cell lines deficient for p53, p16(INK4A), and p14(ARF), FAK was inhibited in a dominant-negative manner by the focal adhesion targeting (FAT) domain, reducing invasion. In addition, caspase-3 activity was increased after serum withdrawal, or by cisplatin in the presence of serum, or upon loss of substrate attachment, and was in each case independent of PTEN status. Our results identify FAK as a potential target for anti-invasive strategies against infiltrating glioma cells.
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PMID:PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). 1147 98

Amplification of the epidermal growth factor receptor (EGFR) gene is found in about 40% of glioblastomas (GBMs) but is rarely detected in GBM cell lines. We confirmed that the exceptional SKMG-3 GBM cell line retained amplified EGFR genes in vitro, and found that these sequences were concentrated on extra-chromosomal DNA particles similar to double-minute chromosomes. The cells contained two other gene mutations that are associated with high-grade astrocytic tumors: extra-chromosomal amplification of the cyclin-dependent kinase-4 (CDK4) gene and a homozygous mutation within the PTEN tumor suppressor gene. Immunoblots revealed very high levels of EGFR, moderately increased expression of CDK4, and no detectable PTEN protein. The overexpressed SKMG-3 EGFRs responded to exogenous ligand and resembled normal rather than mutant receptors. A heterozygous mutation of the p53 gene (p53R282W) correlated with failure of radiation to induce the expression of cyclin-dependent kinase inhibitor p21waf1 or an early G1 cell cycle arrest. Although each of these gene mutations occurs in GBMs, SKMG-3 cells had an unusual genotype in that a p53 gene mutation co-existed with amplified EGFR genes. Nonetheless, the SKMG-3 cell line can be exploited as a model to study how oncogenic EGFR signals in GBM cells interact with over-expressed CDK4 and loss of PTEN to confer the malignant phenotype.
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PMID:Glioblastoma-related gene mutations and over-expression of functional epidermal growth factor receptors in SKMG-3 glioma cells. 1151 90

PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.
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PMID:Regulation of PTEN transcription by p53. 1154 34

Glioblastomas may develop de novo (primary glioblastomas) or through progression from low-grade or anaplastic astrocytomas, (secondary glioblastomas). These subtypes of glioblastoma constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and are likely to differ in prognosis and response to therapy. Primary glioblastomas develop in older patients and typically show EGFR overexpression, PTEN (MMAC1) mutations, CDKN2A (p16) deletions, and less frequently, MDM2 amplification. Secondary glioblastomas develop in younger patients and often contain TP53 mutations as the earliest detectable alteration. These characteristics are derived largely from patients selected on the basis of clinical history and sequential biopsies. Currently available data are insufficient for a substitution of histologic classification and grading of astrocytic tumors by genetic typing alone. More subtypes of glioblastomas may exist with intermediate clinical and genetic profiles, a factor exemplified by the giant-cell glioblastoma that clinically and genetically occupies a hybrid position between primary (de novo) and secondary glioblastomas. Future research should aim at the identification of criteria for a combined clinical, histologic, and genetic classification of astrocytic tumors.
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PMID:Primary and secondary glioblastomas: from concept to clinical diagnosis. 1155 Mar 1

Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.
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PMID:Glioblastomas with an oligodendroglial component: a pathological and molecular study. 1155 43

The generation of transgenic mice overexpressing activated forms of oncogenes has greatly advanced our understanding into their roles in mammary tumor initiation, promotion and progression. However, targeted disruption of tumor suppressor genes often results in lethality at stages prior to mammary tumor formation. This obstacle can now be overcome using several approaches including conditional knockouts that delete genes of interest in a spatial and temporal manner. This review summarizes recent studies on tumor suppressor genes, including APC, ATM, BRCA1, BRCA2, PTEN and p53, in knockout mouse models and our understanding of the possible mechanisms underlying mammary tumorigenesis.
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PMID:Knockout mouse models and mammary tumorigenesis. 1156 81


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