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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor p53 prevents tumour formation after DNA damage by halting cell cycle progression to allow DNA repair or by inducing apoptotic cell death. Loss of wild-type p53 function renders cells resistant to DNA damage-induced cell cycle arrest and ultimately leads to genomic instabilities including gene amplifications, translocations and aneuploidy. Some of these chromosomal lesions are based on mechanisms that involve recombinatorial events. Here we report that p53 physically interacts with key factors of homologous recombination: the human RAD51 protein and its prokaryotic homologue RecA. In vitro, wild-type p53 inhibits defined biochemical activities of RecA protein, such as three-way DNA strand exchange and single strand DNA-dependent ATPase activity. In vivo, temperature-sensitive p53 forms complexes with RAD51 only in wild-type but not in mutant conformation. These observations suggest that functional wild-type p53 may select directly the appropriate pathway for DNA repair and control the extent and timing of the production of genetic variation via homologous recombination. Gene amplification an other types of chromosome rearrangements involved in tumour progression might occur not only as result of inappropriate cell proliferation but as a direct consequence of a defect in p53-mediated control of homologous recombination processes due to mutations in the p53 gene.
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PMID:p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. 861 46

The yeast RAD52-dependent pathway is involved in DNA recombination and double-strand break repair. Yeast ubiquitin-conjugating enzyme UBC9 participates in S- and M-phase cyclin degradation and mitotic control. Using the human RAD52 protein as the "bait" in a yeast two-hybrid system, we have identified a human homolog of yeast UBC9, designated UBE2I, that interacts with RAD52, RAD51, p53, and a ubiquitin-like protein UBL1. These interactions are UBE2I-specific, since another DNA repair-related ubiquitin-conjugating enzyme, RAD6 (UBC2), does not interact with these proteins. The interaction of UBE2I with RAD52 is mediated by RAD52's self-association region. These results suggest that the RAD52-dependent processes, cell cycle control, p53-mediated pathway(s), and ubiquitination interact through human UBE2I.
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PMID:Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system. 892 90

The human RAD51 protein is a homologue of the bacteria RecA and yeast RAD51 proteins that are involved in homologous recombination and DNA repair. RAD51 interacts with proteins involved in recombination and also with tumor suppressor proteins p53 and breast cancer susceptibility gene 1 (BRCA1). We have used the yeast two-hybrid system to clone murine cDNA sequences that encode two RAD51-associated molecules, RAB22 and RAB163. RAB163 encodes the C-terminal portion of mouse BRCA2, the homologue of the second breast cancer susceptibility gene protein in humans, demonstrating an in vitro association between RAD51 and BRCA2. RAB22 is a novel gene product that also interacts with RAD51 in vitro. To detect RAD51 interactions in vivo, we developed a transient nuclear focus assay that was used to demonstrate a complete colocalization of RAB22 with RAD51 in large nuclear foci.
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PMID:RAB22 and RAB163/mouse BRCA2: proteins that specifically interact with the RAD51 protein. 919 68

Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene. The nuclear protein BRCA1 has the properties of a transcription factor, and can interact with the recombination and repair protein RAD51. Young women with germline alterations in BRCA1 develop breast cancer at rates 100-fold higher than the general population, and BRCA1-null mice die before day 8 of development. However, the mechanisms of BRCA1-mediated growth regulation and tumour suppression remain unknown. Here we show that BRCA1 transactivates expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in a p53-independent manner, and that BRCA1 inhibits cell-cycle progression into the S-phase following its transfection into human cancer cells. BRCA1 does not inhibit S-phase progression in p21-/- cells, unlike p21+/+ cells, and tumour-associated, transactivation-deficient mutants of BRCA1 are defective in both transactivation of p21 and cell-cycle inhibition. These data suggest that one mechanism by which BRCA1 contributes to cell-cycle arrest and growth suppression is through the induction of p21.
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PMID:Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. 929 97

Normal diploid cells have a limited replicative potential in culture, with progressively increasing interdivision time. Rarely, cell lines arise which can divide indefinitely; like tumor cells, such "immortal" lines display frequent chromosomal aberrations which may reflect high rates of recombination. Recombination frequencies within a plasmid substrate were 3.5-fold higher in nine immortal human cell lines than in six untransformed cell strains. Expression of HsRAD51, a human homolog of the yeast RAD51 and Escherichia coli recA recombinase genes, was 4.5-fold higher in immortal cell lines than in mortal cells. Stable transformation of human fibroblasts with simian virus 40 large T antigen prior to cell immortalization increased both chromosomal recombination and the level of HsRAD51 transcripts by two- to fivefold. T-antigen induction of recombination was efficiently blocked by introduction of HsRAD51 antisense (but not control) oligonucleotides spanning the initiation codon, implying that HsRAD51 expression mediates augmented recombination. Since p53 binds and inactivates HsRAD51, T-antigen-p53 association may block such inactivation and liberate HsRAD51. Upregulation of HsRAD51 transcripts in T-antigen-transformed and other immortal cells suggests that recombinase activation can also occur at the RNA level and may facilitate cell transformation to immortality.
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PMID:Elevated recombination in immortal human cells is mediated by HsRAD51 recombinase. 937 47

We demonstrate by western analysis that the expression levels of TP53 (formerly known as p53), CDKN1A (formerly known as p21Waf1), CDC2 (formerly known as p34cdc2), CCNB1 (cyclin B1) and RAD51 are significantly modulated in confluent, density-inhibited human diploid cell populations exposed to doses where only a small fraction of the nuclei are actually traversed by an alpha-particle track. The extent of modulation of TP53 and CDKN1A is significantly reduced in the presence of the gap junction inhibitor lindane and in irradiated low-density cell populations. In situ immunofluorescence studies show that at doses where about 2% of the nuclei would be traversed by an alpha particle, induction of CDKN1A occurs in more cells than predicted. Furthermore, the induced cells are present in isolated aggregates of neighboring cells. Therefore, our studies at the gene expression level indicate that similar signaling pathways are induced in bystander cells that are not traversed by an alpha particle as in traversed cells, and that biological effects in cell populations are not restricted to the response of individual cells to the DNA damage they receive.
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PMID:Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles. 1019 May 6

Germ-line mutations in the human BRCA2 gene confer susceptibility to breast cancer. Efforts to elucidate its function have revealed a putative transcriptional activation domain and in vitro interaction with the DNA repair protein RAD51. Other studies have indicated that RAD51 physically associates with the p53 tumor suppressor protein. Here we show that the BRCA2 gene product is a 460-kDa nuclear phosphoprotein, which forms in vivo complexes with both p53 and RAD51. Moreover, exogenous BRCA2 expression in cancer cells inhibits p53's transcriptional activity, and RAD51 coexpression enhances BRCA2's inhibitory effects. These findings demonstrate that BRCA2 physically and functionally interacts with two key components of cell cycle control and DNA repair pathways. Thus, BRCA2 likely participates with p53 and RAD51 in maintaining genome integrity.
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PMID:The BRCA2 gene product functionally interacts with p53 and RAD51. 981 93

Induced cell cycle delays were among the first described cellular responses to ionizing radiation (IR). To understand the sensitivity and the molecular events involved in the response to low doses of IR and to examine the role of p53 and its downstream effector p21Waf1, we measured changes in expression of genes postulated to be involved in the cellular response to IR. Expression levels were examined in normal human diploid fibroblasts irradiated and maintained in quiescent density-inhibited growth up to 24-48 h after exposure to X-ray doses as low as 0.1-0.3 Gy, which have negligible effects on cell survival. Among 31 genes analyzed, we observed down-regulation in response to IR of the mRNA levels of CDC2, cyclin A, cyclin B, thymidine kinase, topoisomerase IIalpha, and RAD51. A similar reduction in the expression levels of these genes occurred when irradiated cells were released from confluence and allowed to proliferate. This was not observed in cells in which p53 function was defective and up-regulation of p21Waf1 levels either did not occur (E6 transfected normal human fibroblasts and Li-Fraumeni fibroblasts) or was delayed (ataxia telangiectasia fibroblasts) after irradiation. Down-regulation was also absent in p21Waf1-null mouse embryo fibroblasts (MEFs) but occurred at a lower level in p53-null MEFs, due to slight increases in p21Waf1 levels by a p53-independent pathway. These findings indicate that the down-regulation of these cell cycle regulated genes in irradiated cells is p53-dependent and involves its effector p21Waf1. Although no down-regulation in the expression of genes involved in G2-M was observed in p53 or in p21Waf1-null MEFs, these cells showed a G2-M delay after irradiation, indicating that the expression levels of these genes does not regulate the G2-M delay.
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PMID:Regulation by ionizing radiation of CDC2, cyclin A, cyclin B, thymidine kinase, topoisomerase IIalpha, and RAD51 expression in normal human diploid fibroblasts is dependent on p53/p21Waf1. 983 Dec 41

Information concerning the function of recombination proteins in mammalian cells has been obtained from biochemical studies, but little is known about their mechanisms of action in growing cells. The eukaryotic recombination protein RAD51, a homologue of the Escherichia coli RecA protein, has been shown to interact with various proteins, including the p53 protein, the guardian of genomic stability maintenance. Here, the hamster RAD51 protein, CgRAD51, has been overexpressed in the SPD8 cell line, derived from Chinese hamster V79 cells. This cell line offers unique possibilities for studying different mechanisms for homologous recombination on endogenous substrates. We report that the SPD8 cell line contains a mutated p53 gene, which provides new insights into the recombination process in these cells. The present study demonstrates that overexpression of CgRAD51 in these cells results in a two- to threefold increase in endogenous recombination. In addition, sequence analysis indicated that RAD51 promotes homologous recombination by a chromatid exchange mechanism.
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PMID:The RAD51 protein supports homologous recombination by an exchange mechanism in mammalian cells. 1037 64

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. BRCA1 contains several functional domains that interact directly or indirectly with a variety of molecules, including tumor suppressors (p53, RB, BRCA2 and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell-cycle regulators (cyclins and cyclin-dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtIP) and others. Mounting evidence indicates that these physical associations are not artifacts; rather, BRCA1 is likely to serve as an important central component in multiple biological pathways that regulate cell-cycle progression, centrosome duplication, DNA damage repair, cell growth and apoptosis, and transcriptional activation and repression. This review examines our understanding of the significance of the interactions between BRCA1 and other proteins, through which BRCA1 maintains genome integrity and represses tumor formation. Published 2000 John Wiley & Sons, Inc.
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PMID:Roles of BRCA1 and its interacting proteins. 1091 3


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