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

In intact cells, hsp70 proteins selectively complex with mutant p53. We report here that rabbit reticulocyte lysate contains hsp70 which selectively complexes with the mutant p53 translated in vitro. Hsp70 complexes with dimers and possibly monomers of p53 in a manner that requires the terminal 28 amino acids of p53. Using murine p53Val135, which is temperature-sensitive for phenotype, we demonstrate that p53-hsp70 complexes can occur after post-translational switching from wild-type to mutant p53 phenotype. Moreover, the temperature-induced switch of full-length p53Val135 from wild-type to mutant phenotype is ATP-independent, whereas the switch from mutant to wild-type form requires ATP hydrolysis and involves hsp70. These results imply that hsp70 is involved in the regulation of p53 conformation.
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PMID:Interaction of heat-shock protein 70 with p53 translated in vitro: evidence for interaction with dimeric p53 and for a role in the regulation of p53 conformation. 139 54

Products of a number of mutant p53 genes bind with high affinity to members of the hsp70 family of chaperonin proteins, whereas wild type p53 lacks this type of association. Examination of the sequences of p53 genes from five different species enabled us to predict domains on p53 which may be involved in the association with hsp70 family members. A synthetic polypeptide (Pro-17-Gly) corresponding to the candidate hsp70 binding domain bound to in vitro translated hsp70 as determined by affinity chromatography and nondenaturing gel mobility shift assays. In addition, the Pro-17-Gly peptide competitively inhibited association between hsp70 and p53, an activity which was determined by immunoprecipitation with anti-p53 monoclonal antibody PAb240. The data indicate that p53 contains a hsp70 binding domain, which is located in a highly conserved region at the amino terminus of the protein, and may participate in the cellular function of wild-type p53 or in the transforming capacity of p53 mutants.
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PMID:hsp70 binds specifically to a peptide derived from the highly conserved domain (I) region of p53. 156 24

The viral oncoprotein of simian virus 40, large T antigen (T-ag), is essential for viral replication and cellular transformation. To understand the mechanisms by which T-ag mediates its multifunctional properties, it is important to identify the cellular targets with which it interacts. A cellular protein of 73 kilodaltons (p73) which specifically associates with T-ag in simian virus 40-transformed BALB/c 3T3E cells has been identified. The binding of p73 to T-ag was demonstrated by coimmunoprecipitation analyses using polyclonal and monoclonal antibodies specific for T-ag. The interaction of p73 with T-ag was independent of T-ag complex formation with the cellular protein p53. Partial V8 protease cleavage maps for p73 and the cellular heat shock protein hsp70 were identical. Immunoblot analyses indicated that p73 complexed to T-ag was antigenically related to hsp70. T-ag deletion mutants were constructed that remove internal, amino-terminal, and carboxy-terminal sequences. These mutants mapped the p73 binding domain to the amino terminus of T-ag. The specific dissociation of p73 from the p73/T-ag complex was mediated by ATP; GTP, CTP, and UTP were also utilized as substrates. These characteristics suggest that p73 may be a member of the hsp70 family of heat shock proteins. The biologic significance of p73/T-ag complex formation has yet to be determined.
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PMID:Association of a cellular heat shock protein with simian virus 40 large T antigen in transformed cells. 276 Sep 86

A rabbit antiserum was prepared against the C-terminal peptide of 21 amino acids from the human heat shock protein hsp70. These antibodies were shown to be specific for this highly inducible heat shock protein (72 kilodaltons [kDa] in rat cells), and for a moderately inducible, constitutively expressed heat shock protein, hsc70 (74 kDa). In six independently derived rat cell lines transformed by a murine cDNA-genomic hybrid clone of p53 plus an activated Ha-ras gene, elevated levels of p53 were detected by immunoprecipitation by using murine-specific anti-p53 monoclonal antibodies. In all cases, the hsc70, but not the hsp70, protein was coimmunoprecipitated with the murine p53 protein. Similarly, antiserum to heat shock protein coimmunoprecipitated p53. Western blot (immunoblot) analysis demonstrated that the hsc70 and p53 proteins did not share detectable antigenic epitopes. The results provide clear immunological evidence for the specific association of a single heat shock protein, hsc70, with p53 in p53-plus-ras-transformed cell lines. A p53 cDNA clone, p11-4, failed to produce clonable cell lines from foci of primary rat cells transfected with p11-4 plus Ha-ras. A mutant p53 cDNA clone derived from p11-4, SVKH215, yielded a 2- to 35-fold increase in the number of foci produced after transfection of rat cells with SVKH215 plus Ha-ras. When cloned, 87.5% of these foci produced transformed cell lines. SVKH215 encodes a mutant p53 protein that binds preferentially to the heat shock proteins of 70 kDa compared with binding by the parental p11-4 p53 gene product. These data suggest that the p53-hsc70 protein complex could have functional significance in these transformed cells.
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PMID:Immunological evidence for the association of p53 with a heat shock protein, hsc70, in p53-plus-ras-transformed cell lines. 331 6

We report that exposure of cells to a single electric pulse (250-1250 V/cm) results in the rapid and persistent activation of the DNA binding activities of a number of transcription factors, including AP-1, SP1, AP-2, and NF-kappa B, and the transient expression of select members of the fos and jun gene families. Induction of gene expression occurs primarily at the level of transcription, although c-jun expression also appears to be regulated posttranscriptionally. Interestingly, maximal induction of gene expression is detected at electrical field strengths that do not result in pore formation in the plasma membrane and that do not significantly affect cell viability. Exposure of cells to electric pulses does not result in the activation of HSF1 DNA binding activity, or the induction of hsp70 or p53 protein synthesis, indicating that the induction of fos and jun gene expression is not coincident with protein or DNA damage. The results of these studies suggest that electrical pulses may represent a novel mechanism for inducing the activities of multiple transcription factors and the expression of select members of the fos and jun gene families.
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PMID:Activation of multiple transcription factors and fos and jun gene family expression in cells exposed to a single electric pulse. 758 34

Human 293 cells, transformed by and expressing the early region of the adenovirus genome (i.e., E1A and E1B), contain a phase-dense cytoplasmic structure situated in close proximity to the nucleus. Via indirect immunofluorescence studies such structures have been previously shown to contain both the adenovirus E1B (55 kDa) protein as well as the tumor suppressor gene product p53. Here we show that such structures also stain positive for the cytoplasmic hsp 70 proteins. Such phase-dense structures containing hsp 70, p53, and adenovirus E1B are not unique to 293 cells but also are observed in rodent cell lines stabily transfected with the early region of the adenovirus genome. Using an antibody against a centrosomal protein, pericentrin, we show that these cytoplasmic phase-dense structures are in close proximity to the centrosome. Cell fractionation studies revealed such structures to be highly detergent insoluble. However, like the centrosome, the cytoplasmic phase-dense structures could be rendered detergent soluble following treatment of the cells with agents that disrupt the integrity of the cytoskeleton. While the phase-dense structures appear in close proximity to the centrosome in interphase cells, during mitosis the centrosome and the phase-dense bodies separate from one another. Owing to these observations we examined whether hsp70 and p53 might also co-localize with the centrosome in other cell types not expressing the adenovirus E1A/E1B proteins. We show that a portion of both hsp70 and p53 indeed are present within the centrosome in Hela, COS, and 3T3 cells. These observations raise the possibility that components like hsp70 and p53 may participate in the mechanism(s) controlling cell division in mammalian cells.
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PMID:Both viral (adenovirus E1B) and cellular (hsp 70, p53) components interact with centrosomes. 802 Dec 99

In an effort to correlate the biological activity of the p53 protein with its conformation, we analysed 14 p53 mutants representative of the most frequently observed protein alterations in human cancers, at codons 175, 248 and 273 (22% of all mutations thus far reported), all three of which contained a CpG dinucleotide. Strikingly, most of the mutants at codons 248 and 273 did not display any change in their conformation, as probed by monoclonal antibodies PAb240 and PAb1620 or by binding to hsp70 protein. For all 14 mutants tested, we found a strict correlation between the transactivation properties of p53, tested either on RGC sequences or using the WAF-1 promoter, and inhibition of cell proliferation. All these mutants showed nuclear localization. Several mutants, present at a low incidence in human tumours, displayed wild-type activity in all our assays, suggesting that the presence of a mutation is not strictly correlated with p53 protein inactivation in tumours. Further analysis of nine thus far undescribed p53 mutants at codon 175 revealed a wild-type or mutant behaviour. All these results suggest that the occurrence of a mutation is dependent on two criteria: (i) the mutability of a given codon, such as those containing a CpG dinucleotide; (ii) the resulting amino acids, eventually leading to synthesis of a p53 conferring a growth advantage on the cell.
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PMID:Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. 806 26

Transgenic mice carrying the SV40 early region fused to the Drosophila hsp70 promoter developed smooth muscle and bone neoplasms. The smooth muscle tumors appeared in aged mice and were preferentially located on the muzzle or eyelids. Multiple neoplasms were often present and each appeared to be an independent proliferation. In contrast, the bone tumors typically developed in the petrous ridge and had all the features of osteogenic sarcomas, displaying distant metastasis and invasion of the brain. Cells in both types of tumors exhibited nuclear expression of SV40 T antigen. Mice homozygous for the transgene had a shorter latency for appearance of smooth muscle tumors and developed osteosarcomas more frequently than hemizygous mice. This model system implicates the cellular T antigen-binding proteins, such as Rb and p53, in the pathogenesis of bone and soft tissue neoplasms in mice.
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PMID:Smooth muscle and bone neoplasms in transgenic mice expressing SV40 T antigen. 808 93

The tumor suppressor p53 is a nuclear phosphoprotein with characteristics of a transcription factor. It displays sequence-specific DNA binding, contains a potent transactivation domain, and has been implicated as both a transcriptional activator and a repressor. Transcription of the human hsp70 gene is stimulated by adenovirus E1a protein. This E1a transactivation of the hsp70 promoter is mediated by CCAAT binding factor (CBF). It is demonstrated here that p53 both represses transcription from the human hsp70 promoter and also interacts with CBF. Thus, the repression of the hsp70 promoter by p53 may be mediated by direct protein-protein interaction with CBF. These results suggest that protein-protein interaction between p53 and specific transcription factors may be an additional mechanism by which p53 regulates gene expression.
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PMID:Regulation of the human hsp70 promoter by p53. 841

The two tumour suppressor genes that are most commonly inactivated in human cancer are the p53 gene on chromosome 17 and the retinoblastoma (Rb) gene on chromosome 11. Recent studies of both gene products suggest that they are able to act as powerful negative regulators of cell division. The Rb gene seems to exert this activity by physically complexing to a variety of specific transcription factors and inactivating their function. The capacity of Rb protein to bind these factors is regulated by phosphorylation. The Rb protein can therefore be seen to act as a chaperone for these factors. The p53 protein also may act in part by regulating transcription but may also interact directly with the DNA replication apparatus. The growth suppressive function of p53 is induced by DNA damage leading to an attractive model of p53 as an essential checkpoint control. The p53 protein interacts with members of the hsp70 chaperone family which we now show can regulate its function.
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PMID:Tumour suppressor genes and molecular chaperones. 849 91


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