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)

Inactivation of TP53 tumor suppressor gene is the most frequent molecular alteration in NSCLC, involving up to 60% of cases. Furthermore, TP53 mutational spectrum is related to the type of mutagen exposure, as well as racial and/or diet differences. Nearly 95% of TP53 perturbations affect codons included within exons 5-8 which encode for almost the entire DNA-binding domain. In this study we addressed the possible prognostic value of the molecular alterations identified in exons 5-8 of the TP53 gene in DNAs from 151 paraffin-embedded NSCLC sections corresponding to 59 Spanish and 92 Polish stage I-IIIA resected patients. PCR/single-strand conformation polymorphism (SSCP) analysis revealed that the occurrence of TP53 exon 5-8 mutations was 17/59 (29%) in the Spanish cohort and 17/92 (18%) in the Polish group. However, when DNA sequencing analysis was performed, these frequencies were reduced because of the presence of SSCP-false positive, intronic and silent mutations and polymorphisms. Fifteen of the 59 Spanish NSCLC tumors (25%) harbored TP53 mutations affecting exons 5-8 coding sequences, whereas only 12 of 92 Polish neoplasms (13%) contained alterations in the central hydrophobic region of p53. Our results indicate that the occurrence of TP53 mutations affecting exon 5-8 coding sequences in some European NSCLC populations may be lower than previously reported, and that the TP53 mutational patterns of these cohorts differ somewhat. The Spanish NSCLC patients contained missense mutations (9/59, 15%) and a relatively high percentage of null mutations (5/59, 8%) while the Polish patients mostly harbored missense mutations (9/92, 10%) and only one tumor contained a null type (1/92, 1%). Moreover, most TP53 missense mutations in the Spanish group were located outside the conserved regions, whereas the same mutations in the Polish group affected conserved amino acids. Furthermore, the Polish patients harbored a high percentage of G-->A transitions (most of them at non-CpG sites), while G-->T transversions were predominant in the Spanish group. Our findings suggest that there may be different racial or exogenous factors in these two populations which may help to explain both the distinct TP53 mutational pattern and the lower frequency obtained in the Polish group. The presence of missense mutations did not confer a worse clinical outcome in these subsets of NSCLC patients. However, patients whose tumors contained null TP53 gene mutations had a 5 month median disease-free survival time in contrast with 42 months in those patients without mutations (P=0.008). These findings suggest that loss of p53 function may enhance tumor progression in NSCLC patients independently of whether dominant negative TP53 missense mutations are present.
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PMID:TP53 mutational pattern in Spanish and Polish non-small cell lung cancer patients: null mutations are associated with poor prognosis. 941 38

The Wilms tumor gene WT1 has been implicated in the early development of the kidney. Mutations in WT1 are found in a small fraction of Wilms tumor, a pediatric nephroblastoma, and Denys-Drash syndrome, characterized by genitourinary abnormalities. The WT1 gene product functions as a transcriptional repressor of growth factor-related genes. The kidney is one of the major sites of insulin action in vivo and expresses high levels of insulin receptors (IR). IR expression has been detected during early embryogenesis, suggesting that it may play a role in development. We investigated whether two WT1 splice variants lacking or including a three-amino-acid (KTS) insertion between the third and fourth zinc finger in the DNA-binding domain could repress the IR promoter in vitro. We show that the +KTS variant effectively represses promoter activity under all conditions tested but the -KTS variant was only able to repress in the presence of cotransfected C/EBP beta or a dominant-negative p53 mutation. Deletional mapping indicated that distinct regions of the IR promoter mediated the effects of the two isoforms and DNaseI footprint analysis identified potential WT1 binding sites within these regions.
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PMID:Differential effects of Wilms tumor WT1 splice variants on the insulin receptor promoter. 944 65

The p53 gene has been either mutated or deleted in most human tumors examined to date. Mutations in the specific DNA-binding domain are the most common p53 mutations and are of interest because they may produce p53 molecules with transcriptional capabilities unlike those of the wild-type (WT) p53 protein. Mutations in the rat p53 gene were found in hepatic neoplasms of carcinogen-treated transgenic rats that express simian virus 40 (SV40) large T-antigen (TAg). Because this result was unexpected, we examined some of the biochemical and biological properties of the mutant proteins. Corresponding nucleotide changes were made by site-directed mutagenesis of the rat p53 cDNA, which was then inserted into a eukaryotic expression vector and transfected into the human hepatocyte cell line Hep 3B. Four of the mutant p53 molecules from rat hepatomas retained a strict WT conformation. Two others existed in both WT and mutant conformations. All of the mutant proteins were able to bind TAg as well as WT p53 did. Whereas the WT p53 protein was able to repress expression of a reporter gene containing a p53-response element (pSV2CAT), the missense-mutant p53 proteins induced transcription of the reporter to an extent equivalent to that of TAg. The mutant proteins also allowed TAg to induce the pSV2CAT reporter gene. The mutant molecules were able to enhance survival of Hep 3B cells, perhaps by preventing cell death, whereas expression of the WT p53 protein caused a reduction in cell number to nearly 10% of control levels. The results of these experiments suggest that the mutant p53 molecules observed in the carcinogen-treated transgenic rats may have unique properties that are important in carcinogenesis.
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PMID:Characterization of rare p53 mutants from carcinogen-treated albumin-simian virus 40 T-antigen transgenic rats. 949 13

The transcription factor p53 controls the proliferation and survival of cells exposed to DNA damage. The specific DNA-binding domain of p53 (residues 102-292) has a complex tertiary structure that is stabilized by zinc. In this study, we showed that exposure of cultured cells to the membrane-permeable chelator N,N,N', N'-tetrakis(2-pyridylmethyl)ethylenediamine induced wild-type p53 to accumulate in an immunologically "mutant" form (PAb240+, PAb1620-) with decreased DNA-binding activity. Removal of N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine from culture medium allowed p53 to refold into the immunologically wild-type form, followed by a transient increase in DNA binding, expression of the cyclin-dependent kinase inhibitor p21WAF1, and cell-cycle delay in the G1 phase. Thus, modulation of intracellular zinc induced conformational changes in p53 that activated wild-type function, suggesting that metalloregulation may play a role in controlling p53.
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PMID:Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc. 953 52

The crystal structure of the DNA complex of a STAT-1 homodimer has been determined at 2.9 A resolution. STAT-1 utilizes a DNA-binding domain with an immunoglobulin fold, similar to that of NFkappaB and the p53 tumor suppressor protein. The STAT-1 dimer forms a contiguous C-shaped clamp around DNA that is stabilized by reciprocal and highly specific interactions between the SH2 domain of one monomer and the C-terminal segment, phosphorylated on tyrosine, of the other. The phosphotyrosine-binding site of the SH2 domain in each monomer is coupled structurally to the DNA-binding domain, suggesting a potential role for the SH2-phosphotyrosine interaction in the stabilization of DNA interacting elements.
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PMID:Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. 963 Feb 26

Li-Fraumeni syndrome (LFS) is characterized by a high risk of sarcomas, early onset of breast cancer, and a diversity of other cancers occurring as multiple primary tumors in multiple family members. In many families with LFS, germline mutations within the tumor-suppressor gene p53 have been identified. However, mutations in p53 have not been detected in approximately 30% of LFS families. To address the possibility either that p53 mutations were being missed or that another predisposing gene is altered in LFS, we used a variety of methods to accurately determine the p53 status in a large LFS kindred. A transcriptional activation assay on exons 4-10 of p53 excluded a mutation within the DNA-binding domain of p53. Single-stranded conformational-polymorphism analysis, using intronic primers and sequencing of all the coding exons and intron/exon junctions, also yielded no mutations. Finally, linkage analysis excluded potential mutations in the noncoding regions of p53. Our findings exclude the presence of a p53 germline mutation in a classic LFS family.
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PMID:Exclusion of a p53 germline mutation in a classic Li-Fraumeni syndrome family. 970 30

p53 is a tumor suppressor protein that controls cell proliferation by regulating the expression of growth control genes. In a previous study, we identified two proteins, 53BP1 and 53BP2, that are able to bind to wild type but not to mutant p53 via the DNA-binding domain of p53. We isolated cDNAs expressing a full-length human 53BP1 clone, which predicts a protein of 1972 residues that can be detected in the H358 human lung carcinoma cell line. The 53BP1 and 53BP2 genes were mapped to chromosomes 15q15-21 and 1q41-42, respectively. Immunofluorescence studies showed three types of staining patterns for 53BP1 as follows: both cytoplasmic and nuclear, homogeneous nuclear, and a nuclear dot pattern. In contrast, 53BP2 localized exclusively to the cytoplasm, and this pattern did not change upon coexpression of wild type p53. Although our previous study revealed that p53 is not able to bind simultaneously to either 53BP1 or 53BP2 and to DNA carrying a consensus binding site, both 53BP1 and 53BP2 enhanced p53-mediated transcriptional activation and induced the expression of a p53-dependent protein, suggesting that these proteins might function in signal transduction pathways to promote p53 activity.
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PMID:Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2. 974 85

p53 is very often mutated in human cancers. The majority of alterations are missense mutations located within the DNA-binding domain of the protein. Many reports have characterized such mutant proteins. Little is known, however, about the properties of proteins that have a missense mutation outside this domain. We investigated here the properties of 8 mutant proteins identified in human tumors as having a missense mutation in the tetramerization domain. The Arg342Gln, Glu349Asp and Gln354Arg proteins behaved like wild-type both in vitro and in cells. Two mutants, Arg342Pro and Leu344Pro, were inactive in all assays. Finally, the 3 mutant proteins Leu330His, Arg337Cys and Arg337Leu, which are inactive in vitro, showed no activity at low expression levels in cells but became active at higher expression levels. Our results reveal new phenotypes for p53 mutants and suggest that sequencing of the p53 gene from patients with tumors should be extended to exons 9 and 10 in clinical investigations.
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PMID:Characterization of p53 mutants identified in human tumors with a missense mutation in the tetramerization domain. 976 74

Germline mutations of the p53 gene are associated to the Li-Fraumeni, a rare autosomal dominant syndrome characterized by a wide spectrum of tumours including sarcomas, breast carcinomas, brain tumors and adrenocortical carcinomas. In most of the cases, tumours will develop in children and young adults. Germline p53 mutations have been identified in approximately 50% of the families with the Li-Fraumeni syndrome, and in families which only partially fulfilled the definition of the syndrome. Germline p53 mutations are mostly missense mutations, located between exon 5 and exon 8, within the DNA-binding domain of p53 and these mutations inactivate the transcriptional activity of the protein. In tumours, the wild-type allele is usually lost, which indicates, that p53 inactivation fits the Knudson model. Identification of a germline p53 mutation in an affected subject allows to establish the diagnosis of the Li-Fraumeni syndrome on a molecular basis and screening for germline p53 mutations may be performed in 1) families including two first degree relatives with cancers belonging to the Li-Fraumeni spectrum, one relative being affected before age 45, 2) children or young adults with a rare tumour of in the general population, belonging to the Li-Fraumeni spectrum, such as adrenocortical carcinoma, and 3) children or young adults under age 45 with multiple primary tumours of the Li-Fraumeni spectrum. In contrast, the clinical benefit of identifying germline p53 mutations carriers in affected families, considering the wide spectrum of tumours associated to this syndrome, remains to be established.
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PMID:[Germline mutations of the p53 gene]. 976 48

Thyroid hormone nuclear receptors (TRs) are ligand-dependent transcription factors which regulate growth, differentiation, and development. The molecular mechanism by which TRs mediated these effects remains unclear. A prevailing hypothesis is that TRs exert their biological effects by cooperating with other transcription factors. We have recently shown that the human TR subtype beta1 (hTRbeta1) interacts with the tumor suppressor p53, which plays a critical role in cell-cycle regulation and tumorigenesis. This interaction of hTRbeta1 with p53 leads to an impairment of TR function. The present study examined whether hTRbeta1 could modulate the function of p53. Mapping of the domains of p53 responsible for the interaction with hTRbeta1 indicated that the regions involved resided in the DNA-binding domain and carboxy terminus of p53. In agreement with this finding, hTRbeta1 increased the binding of p53 to p53 DNA-binding elements. This increase in DNA binding, however, resulted in repression of p53-dependent transcription activation in transfected cells. Furthermore, hTRbeta1 led to an inhibition of the p53-mediated induction of bax and gadd45 expression. In contrast, the p53-induced expression of p21 was not affected by hTRbeta1, suggesting that the expression of p53-regulated genes is differentially modulated by hTRbeta1. Because the expressions of bax, gadd45, and p21 are directly regulated by p53, these results indicate that hTRbeta1 can modulate p53-regulated gene expression and support the hypothesis that there is cross-talk between these two regulatory pathways. The cross-talk between these two transcription factors could play an important role in the biology of normal and cancer cells.
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PMID:Thyroid hormone receptor is a negative regulator in p53-mediated signaling pathways. 977 33


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