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

The formation of complexes between oncoproteins of DNA tumor viruses and the cellular protein p53 is thought to result in inactivation of the growth suppressor function of p53. In cells transformed by nononcogenic human adenovirus type 5 (Ad5), the 55-kDa protein encoded by E1B forms a stable complex with p53 and sequesters it in the cytoplasm. However, the homologous 54-kDa protein of highly oncogenic Ad12 does not detectably associate with p53. Yet in Ad12-transformed cells, p53 is metabolically stable, is present at high levels in the nucleus, and contributes to the oncogenicity of the cells. Such properties have previously been described for mutant forms of p53. Here, we show that stable p53 in Ad12-transformed cells is wild type rather than mutant and that stabilization of p53 is a direct consequence of the expression of the Ad12 E1B protein. We also compared the effects of the E1B proteins on transformation of rodent cells by different combinations of oncogenes. A synergistic interaction was observed for the gene encoding the 54-kDa E1B protein of Ad12 with myc plus ras oncogenes, resembling the effect of mutant p53 on myc plus ras. In contrast, the Ad5 55-kDa E1B protein strongly inhibited transformation by myc plus ras but stimulated transformation by E1A plus ras. The data are explained in terms of different interactions of the two E1B proteins with endogenous p53. The results suggest that in cultured rat cells, endogenous wild-type p53 plays an essential role in cell proliferation, even in the presence of myc plus ras. The dependence on p53 is lost, however, when the adenovirus E1A oncogene is present.
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PMID:Large E1B proteins of adenovirus types 5 and 12 have different effects on p53 and distinct roles in cell transformation. 835 Mar 96

The protein encoded by the tumour-suppressor gene p53 can complex with SV40 virus large T antigen, the adenovirus E1B 58-kDa protein and the E6 protein of human papillomavirus type 16. The functions of these complexes are unclear, but there is some evidence to suggest that binding of p53 to these viral proteins may inactivate p53 function. Recent reports have shown that p53 is involved in regulation of transcription. We have considered the possibility that p53 may regulate transcription of viral genes important for virus replication and/or transformation. Inactivation of p53 function by formation of such complexes might then permit correct expression of these viral genes. Since p53 can bind to the SV40 virus enhancer/promoter, we have investigated the effect of p53 on transcription from this promoter and report here that mouse p53 is a potent repressor of the SV40 enhancer/promoter. Mutations within p53 severely inhibited this activity and provided some evidence to show that the N-terminus of p53 contains residues essential for this function. We also show that mouse p53 represses transcription from the promoters of viruses that do not express proteins that complex with p53: the human cytomegalovirus early promoter and the Rous sarcoma virus long terminal repeat. By studying the effect of p53 on transcription in different cell lines, we show that the effects of p53 on promoters may be cell type specific.
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PMID:Wild-type mouse p53 down-regulates transcription from different virus enhancer/promoters. 838 57

Oncogenic transformation by human adenoviruses requires early regions 1A and 1B (E1A and E1B) and provides a model of multistep carcinogenesis. This study shows that the metabolic stabilization of p53 observed in adenovirus 5 (Ad5)-transformed cells can occur in untransformed cells expressing E1A alone. Stabilized p53 was localized to the nucleus and was indistinguishable from wild-type p53 with respect to its interactions with hsc70, PAb420, Ad5 p55E1B, and SV40 large T antigen. Moreover, binding of Ad5 p55E1B or SV40 large T antigen had no additional effect on p53 levels or turnover. Higher levels of p53 were also induced in a variety of cell types within 40 hr after transferring E1A genes. E1A also caused cells to lose viability by a process resembling apoptosis. The apoptosis appeared to involve p53, because p53 levels reverted to normal in surviving cells that had lost E1A, and E1B protected cells from the toxic effects of E1A. These results suggest that (1) the involvement of p53 in tumor suppression and/or apoptosis can be regulated at the level of protein turnover, and (2) a major oncogenic role for E1B is to counter cellular responses to E1A (i.e., stabilization of p53 and associated apoptosis) that preclude transformation by E1A alone. This represents the first physiological setting in which high levels of endogenous p53 are induced in response to an oncogenic challenge, with the apparent consequence of suppressing transformation.
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PMID:Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. 838 79

Transformation of primary rodent cells by the adenovirus E1A and E1B oncogenes is a two-step process, where E1A-dependent induction of proliferation is coupled to E1B-dependent suppression of programmed cell death (apoptosis). The E1B gene encodes two distinct transforming proteins, the 19K and 55K proteins, both of which independently cooperate with E1A. E1B 19K or 55K protein, or the human Bcl-2 protein, functions to suppress apoptosis and thereby permits transformation with E1A. The E1B 55K protein blocks p53 tumor suppressor protein function, indicating that p53 may mediate apoptosis by E1A. In the mutant conformation, p53 blocked induction of apoptosis by E1A and efficiently cooperated with E1A to transform primary cells. When p53 was returned to the wild-type conformation, E1A+p53 transformants underwent cell death by apoptosis. This induction of apoptosis by conformational shift of p53 from the mutant to the wild-type form was inhibited by expression of the E1B 19K protein. Thus, the p53 protein may function as a tumor suppressor by initiating a cell suicide response to deregulation of growth control by E1A. E1B 19K and 55K proteins provide separate mechanisms that disable the cell suicide pathway of p53.
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PMID:Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. 838 80

The p53 gene is contained within 16-20 kb of cellular DNA located on the short arm of human chromosome 17 at position 17p13.1. This gene encodes a 393-amino-acid nuclear phosphoprotein involved in the regulation of cell proliferation. Current evidence suggests that loss of normal p53 function is associated with cell transformation in vitro and development of neoplasms in vivo. More than 50% of human malignancies of epithelial, mesenchymal, haematopoietic, lymphoid, and central nervous system origin analysed thus far, were shown to contain an altered p53 gene. The oncoproteins derived from several tumour viruses, including the SV40 large T antigen, the adenovirus E1B protein and papillomavirus E6 protein, as well as specific cellular gene products, e.g. murine double minute-2 (MDM2), were found to bind to the wild-type p53 protein and presumably lead to inactivation of this gene product. Therefore, the inactivation of p53 tumour suppressor gene is currently regarded as an almost universal step in the development of human cancers. The current data on p53-associated tumourigenesis are briefly discussed in this minireview.
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PMID:Tumourigenesis associated with the p53 tumour suppressor gene. 839 88

Several protein fusion systems have been used in recent years to study protein-protein and DNA-protein interactions. Most of them use bacterially produced proteins which have several inherent disadvantages, notably, the absence of correct post-translational modifications and the frequent insolubility of recombinant proteins. We sought to develop a system to study proteins interacting with the nuclear phosphoprotein p53, which is believed to be a tumor suppressor. To prepare fusions of p53, we developed a convenient system that permits both in vivo and in vitro production and easy affinity purification of peptides and protein fragments as glutathione-transferase fusions. We placed the coding sequence of the Schistosoma japonica glutathione S-transferase (GST) under the control of the strong CMV/T7 promoter and SV40 splice and polyadenylation signals. An extensive polylinker (MCS) at the 3' end of the GST gene is preceded by the sequence encoding the cleavage site of the site-specific protease. We cloned the complete coding sequences of human wild-type p53, as well as p53 mutants representing all four mutational hotspots (codons 141, 175, 248, and 273), into our expression vector. In vitro transcription using the upstream T7 promoter and translation in reticulocyte lysates form an easy way to produce hybrid proteins; affinity purification on a glutathione-agarose column removes proteins that are present in reticulocyte lysates. We have also studied specific in vivo interactions of human p53 with the adenoviral 55-kDa E1B protein by transfecting expression constructs of GST-p53 fusions into human Ad5-transformed 293 cells.
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PMID:Specific interaction between adenoviral 55-kDa E1B protein and in vivo produced p53 fusion proteins. 840 15

The p53 gene is a 16-20 kb of cellular DNA located on the short arm of human chromosome 17 at position 17p13.1. This gene encodes a 375-amino acid nuclear phosphoprotein which involves in the regulation of cell proliferation. The p53 gene was originally regarded as a dominant oncogene because its overexpression resulted in the immortalization of rodent cells, and the p53 gene could transform rat embryonic fibroblasts in concert with an activated ras gene. It soon became clear, however, that many of the p53 clones that had been studied were in fact mutated versions of the gene, and the wild-type p53 actually acts as a tumor suppressor. Loss of normal p53 function has been associated with the cell transformation in vitro and the development of neoplasms in vivo. More than one-half of human malignancies derived from the epithelial, mesenchymal, hematopoietic, and lymphoid tissues, as well as the central nervous system, analyzed thus far, were shown to contain an altered p53 gene. Most p53 gene alterations are the missense mutations, giving rise to an altered protein. These mutations are most frequently located in the evolutionally conserved areas. Furthermore, it has been demonstrated that the SV40 large T antigen, the adenovirus E1B protein, and papillomavirus E6 protein can bind to wild-type p53 protein and presumably lead to inactivation of this gene product as well. Therefore, the inactivation of normal (or wild-type) p53 is currently regarded as an important genetic pathway for human carcinogenesis generated by endogenous factors and exogenous carcinogens, as well as several tumor viruses. The current data on the p53 gene and its alterations in human malignancies, particularly those in the gastrointestinal tract, are reviewed.
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PMID:The p53 tumor suppressor gene as a common cellular target in human carcinogenesis. 842 17

The expression of p53 in a large panel of adenovirus (Ad) 2/5- and 12-transformed human, rat, and mouse cells has been examined. In all cases, in the absence of the larger Ad E1B protein, the level of p53 is very low. In human and rat cells when the Ad 12 E1B 54K polypeptide is expressed, p53 is much more abundant, although this is not the case in Ad 12 E1-transformed mouse cells. We conclude that expression of p53 is determined by virus serotype, host cell type, and viral proteins expressed. p53 in Ad 12 E1-transformed human cells is wild type but has an extended half-life. Stabilization is not through protein-protein interaction with the Ad E1B protein. The level of expression of c-Myc is also elevated in Ad-transformed human cells but this does not correlate with the presence of the E1B protein or with p53. However, Northern blot analysis indicates a direct correlation between mRNA and protein levels. We conclude that c-Myc is regulated at the transcriptional level, whereas p53 is regulated at the post-translational level in adenovirus transformants.
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PMID:Overexpression of wild-type p53 and c-Myc in human fetal cells transformed with adenovirus early region 1. 846 Apr 77

From previous studies on the induction of DNA synthesis in quiescent primary baby rat kidney cells by adenovirus type 5 (Ad5) E1A deletion mutants, we concluded that induction is prevented only when cellular proteins p300 and pRb are both uncomplexed with E1A (J.A. Howe, J.S. Mymryk, C. Egan, P.E. Branton, and S.T. Bayley, Proc. Natl. Acad. Sci. USA 87:5883-5887, 1990). We have now examined induction by these same mutants in virus lacking the E1B region, so that cellular p53 was no longer complexed to the E1B 55-kDa protein. E1A mutants that fail to bind pRb induced DNA synthesis at a significantly lower level in Ad5 lacking E1B than in Ad5 containing E1B. Apparently, therefore, uncomplexed p53 can partially replace p300 in cooperating with pRb to suppress DNA synthesis in baby rat kidney cells.
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PMID:Induction of the cell cycle in baby rat kidney cells by adenovirus type 5 E1A in the absence of E1B and a possible influence of p53. 847 83

Adenovirus-(Ad)- E1A proteins carry two conserved domains (CR1 and CR2) required for transformation of primary rodent cells and essential for association with cellular proteins, including p105RB, p58cyclin A and p33cdk2. We show that in normal rat kidney 49F (NRK) cell lines expressing various mutant Ad5-E1A genes, CR2-, but not CR-1-, deletion mutants induce a typical transformed phenotype as characterized by morphology, absence of density arrest and loss of serum requirement. This indicates that induction of these transformed properties is a function of CR1. The fact that E1A proteins with deletions in CR2 show a greatly reduced association with RB, cyclin A and p33cdk2 suggests that these associations are dispensable for E1A-mediated transformation of NRK cells. Induction of the transformed properties is accompanied by a CR1-dependent increase in Proliferating Cell Nuclear Antigen and cyclin A gene expression. Elevated mRNA and protein levels of cyclin A were also found in Ad12-E1-transformed NRK cells but not in ras-transformed NRK cells. On the other hand, cyclin D expression is decreased in a CR1-dependent manner. Although Ad5-E1A proteins are sufficient to transform NRK cells, further deregulation of growth is obtained when Ad5-E1B proteins are co-expressed. One of the Ad5-E1B effects is the sequestration of the p53 protein into a cytoplasmic body containing the p53/Ad5-E1B-55 kD complex. Interestingly, in NRK cell lines expressing Ad5-E1B-55 kD, cyclin A could be detected not only in the nucleus but also in the cytoplasmic bodies. These results indicate that the deregulation of cell cycle control by the Adenovirus-E1 region may be due to a CR1-dependent alteration of the expression of cyclins A and D.
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PMID:Increased cyclin A and decreased cyclin D levels in adenovirus 5 E1A-transformed rodent cell lines. 851 Sep 23


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