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)

Biallelic, truncating mutations of the hSNF5/INI1 gene have recently been documented in malignant rhabdoid tumor (MRT), one of the most aggressive human cancers. This finding suggests that hSNF5/INI1 is a new tumor-suppressor gene for which germline mutations might predispose to cancer. We now report the presence of loss-of-function mutations of this gene in the constitutional DNA from affected members but not from healthy relatives in cancer-prone families. Furthermore, a constitutional mutation is documented in a patient with two successive primary cancers. In agreement with the two-hit model, the wild-type hSNF5/INI1 allele is deleted in the tumor DNA from mutation carriers. In all tested cases, DNA from parents demonstrated normal hSNF5/INI1 sequences, therefore indicating the de novo occurrence of the mutation, which was shown to involve the maternal allele in one case and the paternal allele in two other cases. These data indicate that constitutional mutation of the hSNF5/INI1 gene defines a new hereditary syndrome predisposing to renal or extrarenal MRT and to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor. This condition, which we propose to term "rhabdoid predisposition syndrome," may account for previous observations of familial and multifocal cases of the aforementioned tumor types. It could also provide the molecular basis for cases of Li-Fraumeni syndrome without p53 germline mutations.
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PMID:Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. 1052 Dec 99

The SWI/SNF complex is required for the transcription of several genes and has been shown to alter nucleosome structure in an ATP-dependent manner. The tumor suppressor protein p53 displays growth and transformation suppression functions that are frequently lost in mutant p53 proteins detected in various cancers. Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro. The transactivation function of p53 is stimulated by overexpression of hSNF5 and BRG-1 and dominant forms of hSNF5 and BRG-1 repress p53-dependent transcription. Chromatin immunoprecipitation assay shows that hSNF5 and BRG-1 are recruited to a p53-dependent promoter in vivo. Overexpression of dominant negative forms of either hSNF5 or BRG-1 inhibited p53-mediated cell growth suppression and apoptosis. Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control.
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PMID:SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription. 1195 Aug 34

Preimplantation genetic diagnosis (PGD) has recently been offered for couples with an inherited predisposition for late onset disorders. This paper presents the results of PGD for a group of couples at risk for producing children with cancer predisposition. Using a standard IVF procedure, oocytes or embryos were tested for different mutations predisposing to cancer, preselecting and transferring only mutation-free embryos back to the patients. The procedure was performed for patients with predisposition to familial adenomatous polyposis coli (FAP), Von Hippel-Lindau syndrome (VHL), retinoblastoma, Li-Fraumeni syndrome, determined by p53 tumour suppressor gene mutations, neurofibromatosis types I and II and familial posterior fossa brain tumour (hSNF5). Overall, 20 PGD cycles were performed for 10 couples, resulting in preselection and transfer of 40 mutation-free embryos, which resulted in five unaffected clinical pregnancies and four healthy children born by the present time. Despite the controversy of PGD use for late onset disorders, the data demonstrate the usefulness of this approach as the only acceptable option for at-risk couples to avoid the birth of children with an inherited predisposition to cancer, and to have a healthy child.
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PMID:Preimplantation genetic diagnosis for cancer predisposition. 1241 39

The hSNF5 chromatin-remodeling factor is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). A number of studies have shown that hSNF5 re-expression blocks MRT cell proliferation. However, the pathway through which hSNF5 acts remains unknown. To address this question, we generated MRT-derived cell lines in which restoration of hSNF5 expression leads to an accumulation in G(0)/G(1), induces cellular senescence and increased apoptosis. Following hSNF5 expression, we observed transcriptional activation of the tumor suppressor p16(INK4a) but not of p14(ARF), repression of several cyclins and CD44, a cell surface glycoprotein implicated in metastasis. Chromatin immunoprecipitations indicated that hSNF5 activates p16(INK4a) transcription and CD44 down-regulation by mediating recruitment of the SWI/SNF complex. Thus, hSNF5 acts as a dualistic co-regulator that, depending on the promoter context, can either mediate activation or repression. Three lines of evidence established that p16(INK4a) is an essential effector of hSNF5-induced cell cycle arrest. 1) Overexpression of p16(INK4a) mimics the effect of hSNF5 induction and leads to cellular senescence. 2) Expression of a p16(INK4a)-insensitive form of CDK4 obstructs hSNF5-induced cell cycle arrest. 3) Inhibition of p16(INK4a) activation by siRNA blocks hSNF5-mediated cellular senescence. Collectively, these results indicate that in human MRT cells, the p16(INK4a)/pRb, rather than the p14(ARF)/p53 pathway, mediates hSNF5-induced cellular senescence.
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PMID:P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells. 1460 92

Embryonal tumors, the most common group of malignant brain tumors in childhood, are heterogeneous and have been associated with a large number of genetic abnormalities. The aim of this study was to comprehensively analyze loss of heterozygosity (LOH) on regions harboring suppressor genes (PTCH2, PTCH1, APC, PTEN, DMBT1, SUFU, AXIN1, hSNF5/INI1) and to study chromosomal regions in which deletions have been described most frequently (1p, 1q, 11p, 16p, 17p). Twenty-nine children (17 male and 12 female), aged from 1 year 13 years were included in this study. There were 24 medulloblastomas (MB) and 5 supratentorial primitive neuroectodermal tumors (sPNET). Tissue samples from 29 primary and 11 recurrent tumors were analyzed according to the LOH standard procedures, which were extended to include fluorescence in situ hybridization for detection of isochromosome 17q (i(17q)) and direct sequencing ofTP53 exon 4. LOH on 17p was found in 15 out of 29 tumors. FISH analysis identified the presence of i(17q) in 16 tumors. Comparison of LOH analysis and the FISH data indicated that alterations of 17p were related to be the introduction of an i(17q) formation. LOH on 10q and 9q was observed in 4 and 2 cases, respectively, and was associated with alterations of chromosome 17. These results indicated a connection between alterations of PTCH/SHH genes and abnormalities of chromosome 17. A deleted region on 22q, covering the hSNF5/INI1 locus, was observed in 3 tumors. Progression of the molecular changes occurred in 1 case of recurrent medulloblastoma. LOH on 10q and 17p was found in both primary and recurrent tumor, while losses on 11p, 16p, and 16q occurred only in the recurrent tumor. No evidence of alteration in TP53 exon 4 was identified.
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PMID:Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11, 16, 17 and 22. 1558 Oct 23

We report here the mutational analysis of hSNF5/INI1 and TP53 genes performed on 11 specimens of choroid plexus carcinomas (CPC) in which a large number of abnormalities has been detected by molecular biology techniques. Loss of heterozygosity (LOH) analysis performed on six tumors revealed losses on chromosomes 1, 3, 5, 9, 10, 13, 16, 18, and 22. However, there were no abnormalities on 17p and mutations of the TP53 gene have been observed for two tumors comprising exons 5 and 7, respectively. Exon 4 of hSNF5/INI1 was mutated in one tumor with LOH restricted to the hSNF5/INI1 locus. There was no coexistence of mutations in both analyzed genes. Our analysis confirms the presence of the hSNF5/INI1 mutations and proves involvement of TP53 mutations in sporadic cases of CPC.
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PMID:Mutational analysis of hSNF5/INI1 and TP53 genes in choroid plexus carcinomas. 1564 1

Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.
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PMID:Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation. 1630 25

The gene encoding the SNF5/Ini1 core subunit of the SWI/SNF chromatin remodeling complex is a tumor suppressor in humans and mice, with an essential role in early embryonic development. To investigate further the function of this gene, we have generated a Cre/lox-conditional mouse line. We demonstrate that Snf5 deletion in primary fibroblasts impairs cell proliferation and survival without the expected derepression of most retinoblastoma protein-controlled, E2F-responsive genes. Furthermore, Snf5-deficient cells are hypersensitive to genotoxic stress, display increased aberrant mitotic features, and accumulate phosphorylated p53, leading to elevated expression of a specific subset of p53 target genes, suggesting a role for Snf5 in the DNA damage response. p53 inactivation does not rescue the proliferation defect caused by Snf5 deficiency but reduces apoptosis and strongly accelerates tumor formation in Snf5-heterozygous mice.
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PMID:Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complex. 1653 10

The term 'epigenetics' refers to heritable changes in gene function that occur in the absence of any change in DNA sequence. Perturbations of epigenetic gene regulation may play a critical role in the genesis of most, if not all, cancers. These alterations include changes in covalent modifications of DNA and histones as well as non covalent changes in nucleosome positioning. Covalent epigenetic modifications have been the main focus of cancer investigation, perhaps because they are more readily assayed and understood than non covalent modifications. Recently, evidence has emerged demonstrating that perturbation of complexes that remodel the structure of chromatin by mobilizing nucleosomes may have a key role in tumor suppression and oncogenic transformation. For example, Snf5 (Ini1/Baf47/Smarcb1), a core component of the Swi/Snf ATPase chromatin remodeling complex, is a potent tumor suppressor that is specifically inactivated in lethal childhood cancers. Notably, these cancers may serve as a paradigm for epigenetic cancers as, despite their extremely aggressive nature, the majority have an entirely normal karyotype with only microdeletions at the Snf5 locus. Recent investigations have shed light upon the mechanistic basis of Snf5 function by demonstrating that Snf5 and the Swi/Snf complex regulate the cell cycle and cooperate with p53 to prevent oncogenic transformation.
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PMID:Epigenetics and cancer: altered chromatin remodeling via Snf5 loss leads to aberrant cell cycle regulation. 1658 16

hSNF5/Ini1 is a core component of the SWI/SNF complex and the gene is frequently mutated in aggressive pediatric rhabdoid tumors. Mechanisms of the malignant transformation, however, remain poorly understood. We analyzed HeLa cells treated with siRNA to the hSNF5/Ini1 mRNA. The resulting efficient and long-term suppression caused characteristic cell enlargement, cell cycle arrest in G1 phase, and subsequent modest apoptosis. Gene expression profiling of the hSNF5-down-regulated cells by cDNA microarray analysis revealed that a limited number of p53-responsive genes, especially p21, were up-regulated. The p53 protein level was also greatly enhanced, suggesting that loss of hSNF5/Ini1 induces a p53 signaling pathway irrelevant to the chk1/2 phosphorylation pathway. Some rhabdoid tumors with very low or no ARF expression were induced to undergo cell enlargement, growth arrest, and, in one case, apoptosis by ectopic expression of the p14ARF protein. These results may in part account for molecular mechanisms of rhabdoid tumor formation.
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PMID:Knock down of hSNF5/Ini1 causes cell cycle arrest and apoptosis in a p53-dependent manner. 1766 67


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