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

The protein p21 (WAF1, CIP1 or sdi1), induced by the tumour-suppressor protein p53, interacts with and inhibits two different targets essential for cell-cycle progression. One of these is the cyclin-Cdk family of kinases and the other is the essential DNA replication factor, proliferating-cell nuclear antigen (PCNA). We report here that separate domains of p21 are responsible for interacting with and inhibiting the two targets. An amino-terminal domain inhibits cyclin-Cdk kinases and a carboxy-terminal domain inhibits PCNA. Using these separated domains, we have determined that p21 inhibits different biological systems through different targets. The PCNA-binding domain is sufficient for inhibition of DNA replication based on simian virus 40, whereas the Cdk2-binding domain is sufficient for inhibition of DNA replication based on Xenopus egg extract and for growth suppression in transformed human cells.
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PMID:Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. 788 82

The tumour suppressor p53 specifically interferes with the onset of S phase. The mechanism of the growth suppression action of the protein is unclear, though recent evidence points to transcriptional activation and repression functions of the protein. A competing hypothesis suggests that p53 interacts with the DNA replication apparatus and directly interferes with DNA replication. The major evidence for this hypothesis is that p53 interacts with the simian virus 40 (SV40)-encoded protein T antigen and interferes with the ability of T antigen to unwind the SV40 origin of DNA replication, and recruit DNA polymerase alpha to the replication initiation complex. Here we report that p53 physically interacts with and inhibits the function of a cellular DNA replication factor, the single-stranded DNA-binding protein complex RPA.
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PMID:Inhibition of DNA replication factor RPA by p53. 836 31

The tumor suppressor protein p53 activates transcription from promoters with specific p53 binding elements, represses transcription from promoters without such elements and interacts with and inhibits the single-stranded DNA binding activity of the human DNA replication factor RPA. All these activities involve the N terminal 70 amino acids of p53. Dissection of the domains of p53 which bind RPA suggest that multiple sub-domains of the protein synergize to give strong RPA binding. Point-mutations in one of these sub-domains of p53 significantly diminish its ability to interact with RPA. A multimer of a peptide from p53 which includes these residues, or of a peptide from the acidic activation domain of the prototypic trans-activator protein VP16, can itself bind to RPA. Comparison of sequences of these multimeric peptides suggests that aromatic amino acids flanked by negatively charged residues are important for binding RPA. Several alleles of p53 with point mutations in the N terminal region were analysed for their relative abilities to bind RPA, activate or repress transcription, and suppress growth of p53 null SaOs2 and H1299 cells. Both mutants of p53 with decreased RPA binding suppressed cell growth as well as wild-type p53, suggesting that p53 can suppress growth without interacting with RPA. The allele that lost most of the transcription activation function also lost most of its transcription repression activity suggesting that interaction with the same basal transcription factors are involved in both functions. This same allele bound RPA well but was defective in growth suppression. Therefore, transcription activation and/or repression appear to be more important for the growth suppression function of p53 than RPA binding.
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PMID:Loss of transactivation and transrepression function, and not RPA binding, alters growth suppression by p53. 870 May 25

The promoter of the human proliferating cell nuclear antigen (PCNA) gene is activated by the adenovirus oncoprotein E1A 243R in HeLa cells. To understand the effect of this oncoprotein on PCNA expression in cells that are sensitive to oncogenic transformation by adenovirus, we studied the effect of E1A 243R on PCNA promoter-directed reporter gene expression in cloned rat embryo fibroblast (CREF) and primary baby rat kidney cells. In contrast to the results obtained in HeLa cells, E1A repressed the PCNA promoter in both cell-types. Promoter analysis identified a p53-responsive element that mediates E1A-induced repression. Repression required the intact N-terminus of E1A 243R, as shown by the ability of mutant E1A proteins to repress the promoter, and correlated with the p300-binding region of E1A. The adenovirus E1B 19K protein relieved repression by E1A 243R. These results reveal dual pathways for induction of this essential DNA replication factor and suggest a mechanism for oncogenic cooperativity between the E1A and E1B oncoproteins.
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PMID:Dual action of the adenovirus E1A 243R oncoprotein on the human proliferating cell nuclear antigen promoter: repression of transcriptional activation by p53. 1061 24

Eukaryotic cells control the initiation of DNA replication so that origins that have fired once in S phase do not fire a second time within the same cell cycle. Failure to exert this control leads to genetic instability. Here we investigate how rereplication is prevented in normal mammalian cells and how these mechanisms might be overcome during tumor progression. Overexpression of the replication initiation factors Cdt1 and Cdc6 along with cyclin A-cdk2 promotes rereplication in human cancer cells with inactive p53 but not in cells with functional p53. A subset of origins distributed throughout the genome refire within 2-4 hr of the first cycle of replication. Induction of rereplication activates p53 through the ATM/ATR/Chk2 DNA damage checkpoint pathways. p53 inhibits rereplication through the induction of the cdk2 inhibitor p21. Therefore, a p53-dependent checkpoint pathway is activated to suppress rereplication and promote genetic stability.
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PMID:A p53-dependent checkpoint pathway prevents rereplication. 1271 85

A domain-specific disruption was performed on the destruction box sequence of endogenous Geminin gene, an inhibitor of the DNA replication initiation complex, in a human cancer cell line HCT116 resulting in the formation of a protein that was stable in the G1 phase of the cell cycle. Although the total amount of Geminin in asynchronous cultures was not elevated, the G1-specific stabilization of Geminin, diminished chromatin loading of minichromosome maintenance complex, inhibited DNA replication, and resulted in the accumulation of cells in G1. The mutated Geminin suppressed in vivo tumorigenicity and in vitro cell growth. Cells carrying this mutation failed to support the replication of a plasmid bearing the oriP replicator of Epstein-Barr virus. The DNA damage checkpoint pathway was activated in the mutated cells with increased levels of p53 protein and its target, the p21 protein. All these deficits were rescued by overexpression of Cdt1, a replication initiator protein that binds to Geminin. Therefore, alteration of the cell cycle-dependent regulation of endogenous Geminin in human cells without increasing total protein level inhibits DNA replication and suppresses tumor growth.
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PMID:The destruction box of human Geminin is critical for proliferation and tumor growth in human colon cancer cells. 1471 11

Replication licensing ensures once per cell cycle replication and is essential for genome stability. Overexpression of two key licensing factors, Cdc6 and Cdt1, leads to overreplication and chromosomal instability (CIN) in lower eukaryotes and recently in human cell lines. In this report, we analyzed hCdt1, hCdc6, and hGeminin, the hCdt1 inhibitor expression, in a series of non-small-cell lung carcinomas, and investigated for putative relations with G(1)/S phase regulators, tumor kinetics, and ploidy. This is the first study of these fundamental licensing elements in primary human lung carcinomas. We herein demonstrate elevated levels (more than fourfold) of hCdt1 and hCdc6 in 43% and 50% of neoplasms, respectively, whereas aberrant expression of hGeminin was observed in 49% of cases (underexpression, 12%; overexpression, 37%). hCdt1 expression positively correlated with hCdc6 and E2F-1 levels (P = 0.001 and P = 0.048, respectively). Supportive of the observed link between E2F-1 and hCdt1, we provide evidence that E2F-1 up-regulates the hCdt1 promoter in cultured mammalian cells. Interestingly, hGeminin overexpression was statistically related to increased hCdt1 levels (P = 0.025). Regarding the kinetic and ploidy status of hCdt1- and/or hCdc6-overexpressing tumors, p53-mutant cases exhibited significantly increased tumor growth values (Growth Index; GI) and aneuploidy/CIN compared to those bearing intact p53 (P = 0.008 for GI, P = 0.001 for CIN). The significance of these results was underscored by the fact that the latter parameters were independent of p53 within the hCdt1-hCdc6 normally expressing cases. Cumulatively, the above suggest a synergistic effect between hCdt1-hCdc6 overexpression and mutant-p53 over tumor growth and CIN in non-small-cell lung carcinomas.
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PMID:Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1. 1546 99

A cell limits its DNA replication activity to once per cell division cycle to maintain its genomic integrity. Studies in a variety of organisms are elucidating how these controls are exercised. Key amongst these is the regulation of replication initiator proteins such as Cdt1. Cdt1 is present in cells in G1 phase where it is required for initiation of replication. Once origins have fired, Cdt1 is either exported out of the nucleus or degraded, thereby preventing another round of replication. Higher eukaryotes have evolved another redundant mechanism, an inhibitor called geminin, to restrain Cdt1 activity. Studies in multiple organisms have shown that unregulated Cdt1 activity stimulates overreplication of the genome. Interestingly, the same seems to be true when geminin is depleted. The imbalance in the activities of these proteins causes the activation of key checkpoint proteins, the ATM/ATR kinases and the tumor suppressor, p53. This review proposes that a balance between Cdt1 and geminin is important for maintaining genomic stability.
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PMID:Geminin-Cdt1 balance is critical for genetic stability. 1560 56

Human replication protein A (RPA), the primary single-stranded DNA-binding protein, was previously found to be inhibited after heat shock by complex formation with nucleolin. Here we show that nucleolin-RPA complex formation is stimulated after genotoxic stresses such as treatment with camptothecin or exposure to ionizing radiation. Complex formation in vitro and in vivo requires a 63-residue glycine-arginine-rich (GAR) domain located at the extreme C terminus of nucleolin, with this domain sufficient to inhibit DNA replication in vitro. Fluorescence resonance energy transfer studies demonstrate that the nucleolin-RPA interaction after stress occurs both in the nucleoplasm and in the nucleolus. Expression of the GAR domain or a nucleolin mutant (TM) with a constitutive interaction with RPA is sufficient to inhibit entry into S phase. Increasing cellular RPA levels by overexpression of the RPA2 subunit minimizes the inhibitory effects of nucleolin GAR or TM expression on chromosomal DNA replication. The arrest is independent of p53 activation by ATM or ATR and does not involve heightened expression of p21. Our data reveal a novel cellular mechanism that represses genomic replication in response to genotoxic stress by inhibition of an essential DNA replication factor.
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PMID:Novel checkpoint response to genotoxic stress mediated by nucleolin-replication protein a complex formation. 1574 38

The exact duplication of chromosomal DNA during each cell cycle ensures the correct inheritance of genetic material from mother to daughter cells. In eukaryotic cells, DNA replication can occur only when the origin of DNA replication is accurately marked by a group of proteins termed licensing proteins. One such protein is Cdt1, which is recruited first to the origin of DNA replication followed by cell division cycle 6 (Cdc6) and mini-chromosome maintenance proteins (Mcms). We previously reported that NIH3T3 cells overexpressing Cdt1 readily formed tumors in mice. To further investigate its oncogenic mechanism, we generated transgenic mice expressing Cdt1 in thymocytes. Our studies demonstrated that T-cell-directed Cdt1 transgenic mice showed normal T-cell development. However, such transgenic mice developed thymic lymphoblastic lymphoma when crossed with p53 null mice. Furthermore, tumor cells derived from NIH3T3 cells overexpressing Cdt1 displayed numerical and structural chromosomal aberrations in the form of ploidy, double minutes, translocation, inversion, chromosome end-to-end fusion and robertsonian mutation. Collectively, our studies suggest that Cdt1 overexpression most likely contributes to tumorigenecity by causing genomic instability.
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PMID:Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53. 1626 Nov 66


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