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 two tumor suppressor genes, RB and p53, is associated with tumor formation. To elucidate the molecular basis of the tumorigenesis of human osteosarcoma, structural and expressional alterations of these two genes were examined in five human osteosarcoma cell lines, two of which were from Japanese patients. In addition, I analyzed two adenovirus E1A-binding proteins, p107 and p300, putative "tumor suppressor gene products", which share similar properties with the RB protein in binding to the E1A oncoprotein. Detailed analyses of DNA, mRNA, and protein showed that (1) 3 lines including both Japanese lines lost the expression of the RB protein due to either the absence or the alteration of mRNA caused by DNA rearrangement, (2) abnormality of p53 gene was detected in all cell lines : 4 lines lost p53 expression due to either gene loss or the absence of mRNA, and one line expressed an abnormal form of the protein without detectable DNA and mRNA alterations and (3) no significant alteration of p107 or p300 was detected in all cell lines. These results further confirm that inactivating mutations of p53 and RB genes are deeply involved in the carcinogenesis of human osteosarcoma and suggest that p107 and p300 may not play a role in the tumorigenesis.
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PMID:[Roles of tumor suppressor genes in human osteosarcoma cells]. 182 50

In this report we present evidence that simian virus 40 T antigen encodes a biological activity that is functionally equivalent to the transforming activity lost by deletion of the E1A p300-binding region. T-antigen constructs from which the pRb-binding region has been deleted are virtually unable to induce foci of transformed cells in a ras cooperation assay in primary baby rat kidney cells. Nevertheless, such a construct can cooperate with an E1A N-terminal deletion mutant, itself devoid of transforming activity, to induce foci in this assay. The heterologous trans-cooperating activity observed between E1A and T-antigen deletion products is as efficient as trans cooperation between mutants expressing individual E1A domains. The cooperating function can be impaired by a deletion near the N terminus of T antigen. Such a deletion impairs neither the p53-binding function nor the activity of the pRb-binding region.
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PMID:Simian virus 40 large-T antigen expresses a biological activity complementary to the p300-associated transforming function of the adenovirus E1A gene products. 184 72

p53 tumor suppressor protein is required for efficient execution of apoptosis after DNA-damage in many cell systems. Since the oncogene E1a confers susceptibility to DNA-damaging agents and stabilizes p53 protein, we investigate whether the sensitivity to anticancer drugs of E1a-expressing cells was mediated by binding to a specific set of cellular proteins (p60, p105, p107 and p300) and related to the induction of apoptosis and the level of p53 protein. We studied the effect of cisplatin (CDDP), doxorubicin (DOX) and ionizing radiation (RX) on murine keratinocytes (PAM 212) transfected by the wild type E1a oncogene or several E1a mutants which bind to different subsets of cellular proteins. Keratinocytes transfected with the mutant d1787N (which binds to p60, p105, p107 and p300) showed a lethality in response to CDDP (10 micrograms ml-1) fourfold higher than controls and threefold higher in response to DOX and radiation (5 grays). The sensitivity of keratinocytes carrying the mutant NTd1598 (binding to p105, p107 and p60) to DNA-damaging agents was similar to that of control keratinocytes, while mutant d1922/947 (binding only to p300) were resistant to CDDP and RX but sensitive to DOX. Apoptosis (after 24 h) studied by DNA fragmentation and flow cytometry was only observed in cells carrying the wild type E1a or the mutant d1787N. After treatment with DNA-damaging agents, p53 protein expression increased in all the cell lines and no rE1ation to sensitivity to anticancer agents or induction of apoptosis was observed. From these results, we conclude that cell sensitivity to cisplatin and ionizing radiation induced by the E1a oncogene requires binding to p105, p107 and p300 cellular proteins, while sensitivity to Doxorubicin requires binding only to p300. Interestingly, p53 protein levels were related to the binding to the p300 protein. The high levels of p53 after CDDP and DOX in the mutant d1922/947, which are only sensitive to DOX, suggest that E1a oncogene products may induce sensitivity to DNA-damaging agents by p53-related and unrelated pathways.
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PMID:Lack of correlation between p53 protein level and sensitivity of DNA-damaging agents in keratinocytes carrying adenovirus E1a mutants. 765 31

The mechanism of cell cycle withdrawal during terminal differentiation is poorly understood. We report here that the cyclin-dependent kinase (CDK) inhibitor p21Cip1/WAF1 is induced at early times of both keratinocyte and myoblast differentiation. p21Cip1/WAF1 induction is accompanied by a drastic inhibition of total Cdk2, as well as p21Cip1/WAF1-associated CDK kinase activities. p21Cip1/WAF1 has been implicated in p53-mediated G1 arrest and apoptosis. In keratinocyte differentiation, Cip1/WAF1 induction is observed even in cells derived from p53-null mice. Similarly, keratinocyte differentiation is associated with induction of Cip1/WAF1 promoter activity in both wild-type and p53-negative keratinocytes. Induction of the Cip1/WAF1 promoter upon differentiation is abolished by expression of an adenovirus E1A oncoprotein (d1922/947), which is unable to bind p105-Rb, p107, or cyclin A but which still binds the nuclear phosphoprotein p300. Overexpression of p300 can suppress the E1A effect, independent of its direct binding to E1A. Thus, terminal differentiation-induced growth arrest in both keratinocyte and myoblast systems is associated with induction of Cip1/WAF1 expression. During keratinocyte differentiation, Cip1/WAF1 induction does not require p53 but depends on the transcriptional modulator p300.
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PMID:Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation. 777 29

The four principal gut epithelial cell lineages undergo continuous and rapid renewal during a geographically well-organized migration along the crypt-to-villus axis. The molecules that regulate their proliferation and differentiation programs are largely unknown. The large tumor antigen (TAg) of wild-type (wt) simian virus 40 (SV40) and its mutant derivatives represent tools for describing the contributions of regulators of the cell cycle to the proliferative state of each lineage. Expression of SV40 TAgwt in postmitotic, villus-associated enterocytes of transgenic mice causes them to reenter the cell cycle without an apparent effect on their state of differentiation. When human KRAS with a Val-12 substitution ([Val12]KRAS) is coexpressed with SV40 TAgwt in villus enterocytes of bitransgenic animals, the two oncoproteins cooperate to produce dedifferentiation (dysplasia). SV40 mutant d11137 expresses a TAg that is unable to complex with p53 but retains N-terminal transforming functions, including the ability to complex pRB, p107, and p300. When SV40 TAgd11137 is expressed in villus enterocytes, they reenter into the cell cycle. However, coexpression of SV40 TAgd11137 and [Val12]KRAS does not produce dysplastic changes. Thus, the N-terminal 121 residues of TAg are sufficient to perturb the proliferative state of the enterocyte but not to produce detectable changes in the state of differentiation when coexpressed with [Val12]KRAS.
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PMID:Expression of wild-type and mutant simian virus 40 large tumor antigens in villus-associated enterocytes of transgenic mice. 804 20

High levels of the p53 tumor suppressor protein can block progression through the cell cycle. A model system for the study of the mechanism of action of wild-type p53 is a cell line (T64-7B) derived from rat embryo fibroblasts transformed by activated ras and a temperature-sensitive murine p53 gene. At 37 to 39 degrees C, the murine p53 protein is in a mutant conformation and the cells actively divide, whereas at 32 degrees C, the protein has a wild-type conformation and the cells arrest in the G1 phase of the cell cycle. Wild-type simian virus 40 large T antigen and a variety of T-antigen mutants were assayed for the ability to bypass the cell cycle block effected by the wild-type p53 protein to induce colony formation at 32 degrees C. The results indicate that two functions within the amino terminus of T antigen are essential to induce cell growth: (i) the ability to bind to the retinoblastoma protein, Rb, and (ii) the presence of a domain in the first exon that appears to interact with the cellular protein, p300. Thus, the cell cycle arrest triggered by wild-type p53 may be overcome by formation of a T-antigen complex with Rb, p300, or both that could then function to either remove p53-mediated negative growth regulatory signals or promote a positive cell growth signal. Surprisingly, T antigen-p53 complexes are not required to overcome the temperature-sensitive p53 block to the cell cycle in these cells. These data suggest that simian virus 40 T antigen associated with Rb, p300, or both proteins can communicate in a cell with the functions of the wild-type p53 protein.
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PMID:The amino-terminal functions of the simian virus 40 large T antigen are required to overcome wild-type p53-mediated growth arrest of cells. 810 98

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

A novel transcription factor binding element in the human p53 gene promoter has been characterized. It lies about 100 bp upstream of the major reported start site for human p53 gene transcription. On the basis of DNase I footprinting studies, electromobility shift assay patterns, sequence specificity of binding, the binding pattern of purified transcription factors, effects of specific antibodies, and methylation interference analysis we have identified the site as a composite element which can bind both YY1 and NF1 in an independent and mutually exclusive manner. The site is conserved in the human, rat, and mouse p53 promoters. The occupancy of the site varies in a tissue-specific manner. It binds principally YY1 in nuclear extracts of rat testis and spleen and NF1 in extracts of liver and prostate. This may facilitate tissue-specific control of p53 gene expression. When HeLa cells were transiently transfected with human p53 promoter-chloramphenicol acetyltransferase reporter constructs, a mutation in this composite element which disabled YY1 and NF1 binding caused a mean 64% reduction in basal p53 promoter activity. From mutations which selectively impaired YY1 or NF1 binding and the overexpression of YY1 or NF1 in HeLa cells we concluded that both YY1 and NF1 function as activators when bound to this site. In transient cotransfections E1A could induce the activity of the p53 promoter to a high level; 12S E1A was threefold as efficient as 13S E1A in this activity, and YY1 bound to the composite element was shown to mediate 55% of this induction. Overexpressed YY1 was shown to be able to synergistically activate the p53 promoter with E1A when not specifically bound to DNA. Deletion of an N-terminal domain of E1A, known to be required for direct E1A-YY1 interaction and E1A effects mediated through transcriptional activator p300, blocked the E1A induction of p53 promoter activity.
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PMID:YY1 and NF1 both activate the human p53 promoter by alternatively binding to a composite element, and YY1 and E1A cooperate to amplify p53 promoter activity. 881 7

The block of cell proliferation elicited by the addition of nerve growth factor (NGF) to exponentially-growing PC12 cells results, in part, from the inhibition of cyclin D1-associated kinase activity by p21WAF1/CIP1. NGF treatment of PC12 cells provokes the accumulation of p21 mRNA, due to transcriptional activation of the p21 promoter in a p53-independent manner. Transient expression of a mutated form of the adenovirus E1A protein (E1A dCR2), which retains its capacity to bind the transcriptional co-activator p300, completely abolishes the NGF-mediated stimulation of p21 promoter activity. This phenomenon can be reversed by ectopic expression of p300, suggesting that p300 is necessary for the induction of p21 by NGF. In addition, stable expression of E1A dCR2 in PC12 cells results in the inhibition of the NGF response, i.e. it prevents activation of the p21 promoter, cell cycle arrest, and neuronal differentiation. The signalling pathway from the TrkA receptor via the MAP kinase pathway is not altered in these cells. Together, these data indicate that p300 could play a pivotal role in the triggering of the anti-mitogenic effect of NGF and of neuronal differentiation.
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PMID:The CDK inhibitor p21WAF1/Cip1 is induced through a p300-dependent mechanism during NGF-mediated neuronal differentiation of PC12 cells. 895 Sep 71

Several cellular polypeptides critical for growth regulation interact with DNA tumor virus oncoproteins. p400 is a cellular protein which binds to the adenovirus E1A oncoprotein(s). The biological function of p400 is not yet known, but it is structurally and immunologically closely related to p300 and CREB-binding protein, two known E1A-binding transcription adapters. Like p300, p400 is a phosphoprotein that binds to the simian virus 40 large tumor antigen (T). In anti-T coimmunoprecipitation experiments, staggered deletions spanning the amino-terminal 250 amino acids of T did not abrogate T binding to either p400 or p300. A T species composed of residues 251 to 708 bound both p400 and p300, while a T species defective in p53 binding was unable to bind either detectably. Anti-p53 immunoprecipitates prepared from cells containing wild-type T also contained p400 and p300. Hence, both p400 and p300 can bind (directly or indirectly) to a carboxyl-terminal fragment of T which contains its p53 binding domain. Since the p53 binding domain of T contributes to its immortalizing and transforming activities, T-p400 and/or T-p300 interactions may participate in these functions.
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PMID:p300 family members associate with the carboxyl terminus of simian virus 40 large tumor antigen. 898 31


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