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)

The tumour suppressor p53 is a multifunctional protein important for the maintenance of genomic integrity. It is able to form molecular complexes with different DNA targets and also with cellular proteins involved in DNA transcription and DNA repair. In mammalian cells the biochemical processing of DNA occurs on a nuclear sub-structure termed the nuclear matrix. Previously Deppert and co-workers have identified p53 in association with the nuclear matrix in viral- and non-viral transformed cell lines. In the present study we demonstrate, for the first time, that p53 is bound to the nuclear matrix in primary cultures of normal mammalian cells and that this binding increases following DNA damage. Analysis of cell lines expressing structural mutants of p53 revealed that association with the nuclear matrix is independent of the tertiary and quaternary structure of p53. However, the proline-rich domain towards the N-terminus of p53 (residues 67 to 98) appeared important for binding to the nuclear matrix. This was demonstrated by TET-ON regulated expression of p53-derived constructs in p53(-/-) murine embryonic fibroblasts (MEF p53(-/-)). The proline-rich domain of p53 has potential for SH3 protein-protein interaction, and has a role in p53-mediated apoptosis and possibly base excision repair of DNA damage. We discuss our observations in relation to the ability of p53 to facilitate DNA repair and also review evidence indicating that matrix-bound p53 in SV40-transformed cells may facilitate the transforming potential of SV40 large T antigen.
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PMID:p53 binds the nuclear matrix in normal cells: binding involves the proline-rich domain of p53 and increases following genotoxic stress. 1157 42

Transforming growth factor beta (TGF-beta1) suppresses the growth of mink lung Mv1Lu epithelial cells, whereas testicular hyaluronidase abolishes the growth inhibition. Exposure of Mv1Lu cells to TGF-beta1 rapidly resulted in down-regulation of cytosolic IkappaBalpha and hyaluronidase prevented this effect, suggesting a possible role of IkappaBalpha in the growth regulation. Ectopic expression of wild-type and dominant negative IkappaBalpha prevented TGF-beta1-mediated growth suppression. Nonetheless, the blocking effect of IkappaBalpha is not related to regulation of NF-kappaB function by its N-terminal ankyrin-repeat region (amino acids 1-243). Removal of the PEST (proline-glutamic acid-serine-threonine) domain-containing C terminus (amino acids 244-314) abolished the IkappaBalpha function, and the C terminus alone blocked the TGF-beta1 growth-inhibitory effect. Co-immunoprecipitation by anti-p53 antibody using Mv1Lu and other types of cells, as well as rat liver and spleen, revealed that a portion of cytosolic IkappaBalpha physically interacted with p53. In contrast, Mdm2, an inhibitor of p53, was barely detectable in the immunoprecipitates. The cytosolic p53 x IkappaBalpha complex rapidly dissociated in response to apoptotic stress, etoposide- and UV-mediated DNA damage, hypoxia, and TGF-beta1-mediated growth suppression. Also, a rapid increase in the formation of the nuclear p53 x IkappaBalpha complex was observed during exposure to etoposide and UV. In contrast, TGF-beta1-mediated promotion of fibroblast growth failed to mediate p53 x IkappaBalpha dissociation. Mapping by yeast two-hybrid showed that the non-ankyrin C terminus of IkappaBalpha physically interacted with the proline-rich region and a phosphorylation site, serine 46, in p53. Deletion of serine 46 or alteration of serine 46 to glycine abolished the p53 x IkappaBalpha interaction. Alteration to threonine retained the binding interaction, suggesting that serine 46 phosphorylation is involved in the p53 x IkappaBalpha complex formation. Functionally, enhancement of p53 apoptosis was observed when p53 and IkappaBalpha were transiently co-expressed in cells. Together, the IkappaBalpha x p53 complex plays an important role in responses involving growth regulation, apoptosis, and hypoxic stress.
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PMID:The non-ankyrin C terminus of Ikappa Balpha physically interacts with p53 in vivo and dissociates in response to apoptotic stress, hypoxia, DNA damage, and transforming growth factor-beta 1-mediated growth suppression. 1179 6

The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. We found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. Our data indicate that at least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. These data indicate that the two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.
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PMID:The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. 1256 88

The p53 transcription factor contains two separate tandem activation domains (AD1 and AD2), a proline-rich domain (PRD), and a C-terminal basic domain (BD). Previously, we have shown that these domains are necessary for transcriptional activity. To further characterize the role of these domains in transactivation, we analyzed the regulation of p21, a well characterized p53 target gene, by various p53 mutants deficient in one or more of these domains. We found that the induction of endogenous p21 is compromised by AD1-deficient p53 (p53(AD1(-))), AD2-deficient p53 (p53(AD2(-))), both AD1- and AD2-deficient p53 (p53(AD1(-)AD2(-))), p53(deltaPRD), which lacks PRD, and p53(deltaBD), which lacks BD. However, p53(AD2(-)), p53(deltaPRD), and p53(deltaBD) are still capable of activating exogenous p21 promoter to an extent comparable with that by wild-type p53. Thus, we performed chromatin immunoprecipitation assay to measure the DNA binding ability of various p53 mutants in vivo. We found that like wild-type p53, these p53 mutants are capable of binding to the p53 response elements in the p21 promoter. In contrast, we found that the extent of acetylated histones on the p21 promoter, especially the proximal promoter, and the amount of interaction with p300/CREB-binding protein, which contain histone acetyltransferase activity, directly correlate with the activity of p53 to induce endogenous p21. Furthermore, we showed that down-regulation of p300/CBP by short interference RNA markedly decreases the ability of p53 to induce endogenous p21. These data lead us to hypothesize that when p53 binds to the responsive element(s) of a target gene, its ability to interact with histone acetyltransferase-containing proteins and subsequently the acetylation of histones bound to the proximal promoter dictate the induction level of a target gene.
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PMID:The activation domains, the proline-rich domain, and the C-terminal basic domain in p53 are necessary for acetylation of histones on the proximal p21 promoter and interaction with p300/CREB-binding protein. 1260 99

Nuclear localization and high levels of the Y-box binding protein YB1 appear to be important indicators of drug resistance and tumor prognosis. YB1 also interacts with the p53 tumor suppressor protein. In this paper, we explore a role for p53 in the nuclear localization of YB1. We report that various genotoxic stresses induce nuclear localization of YB1 in a small proportion of treated cells, but only in cells with wild-type p53. We go on to show directly that functional p53 is required for YB1 to translocate to the nucleus. Tumor-associated p53 mutants however are attenuated for YB1 nuclear localization as are mutants mutated in the proline-rich domain of p53. These data link the DNA-damage response of p53 to YB1 nuclear translocation. In addition, we find that YB1 inhibits p53-induced cell death and its ability to trans-activate promoters of genes involved in cell death signaling. Together these data suggest that some forms of p53 cause YB1 to accumulate in the nucleus, which in turn inhibits p53 activity. These results provide a possible explanation for the correlation of nuclear YB1 with drug resistance and poor prognosis in some tumor types, and for the first time implicate p53 in the process of nuclear translocation.
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PMID:Nuclear localization of Y-box factor YB1 requires wild-type p53. 1274 1

p73, a p53 family member, is highly similar to p53 in both structure and function. Like p53, the p73 protein contains an N-terminal activation domain, a DNA-binding domain, a tetramerization domain, and several PXXP motifs. Previously, we and others have shown that some functional domains in p53, such as the DNA-binding and tetramerization domains, are required for inducing both cell cycle arrest and apoptosis whereas others, such as the second activation domain, the proline-rich domain, and the C-terminal basic domain, are only required for inducing apoptosis. To determine the activity of p73 functional domains, we have generated stable inducible cell lines that express p73beta and various mutants deficient in one or more functional domains. We found that in addition to the DNA-binding domain, p73-mediated growth suppression requires the N-terminal activation domain and the tetramerization domain. However, unlike p53, p73-mediated apoptosis does not require the region adjacent to the activation domain or the entire C-terminal region. Interestingly, while the N- or the C-terminal PXXP motifs are dispensable for p73 function, deletion of both the N- and the C-terminal PXXP motifs renders p73 inactive in transactivation. In addition, we found that substitution of two conserved tandem hydrophobic residues with two hydrophilic ones, which can abrogate the activity of the first activation domain in p53, has no effect on p73 transcriptional activity. Together, we showed that the p73 protein has its own unique determinants for transactivation and growth suppression.
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PMID:Characterization of p73 functional domains necessary for transactivation and growth suppression. 1285 70

The N-terminal proline-rich domain of human p53 has been shown to be important for the induction of apoptosis. However, the corresponding region in mouse and other species is not highly conserved and has been less well studied. In this paper, we have characterized mutants with deletions in this region of mouse p53. Our results demonstrate that deletions in the proline-rich domain have varying effects on function ranging from no effect to severe impairment of cell death activity, depending on precisely which residues are deleted. We also show that the mutants differ in their ability to transactivate different p53 target promoters. Although we have been able to obtain mutants selectively impaired for apoptosis, our data are not generally consistent with this region being a functional domain. The data are more consistent with the interpretation that the region influences function by altering local protein structure which may affect promoter discrimination.
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PMID:The proline-rich region of mouse p53 influences transactivation and apoptosis but is largely dispensable for these functions. 1288 8

Expression of p73, a p53 family member regulating cell growth and apoptosis, is maintained at low levels in mammalian cells, and cellular activation of p73 is usually controlled at the protein level. However, the precise molecular mechanisms by which p73 stability is regulated are unclear. During the search for interacting molecules with the COOH-terminal proline-rich region of p73, we identified a novel NEDD4-related protein (termed as NEDL2) which contains a C2 domain at its NH(2)-terminus, two WW domains, and a HECT domain at its COOH-terminus. As expected, NEDL2 catalyzed the ubiquitination of bacterial cellular proteins in vitro. Reciprocal co-immunoprecipitation experiments and in vitro pull-down assays revealed that NEDL2 bound to p73, which carries two putative PY motifs. p73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability.
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PMID:A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and enhances its transcriptional activity. 1289 Apr 87

In this study, we used oligonucleotide microarray analysis to determine which cellular genes are regulated by the human papillomavirus type 16 (HPV-16) E6 oncoprotein. We found that E6 causes the downregulation of a large number of cellular genes involved in keratinocyte differentiation, including genes such as small proline-rich proteins, transglutaminase, involucrin, elafin, and cytokeratins, which are normally involved in the production of the cornified cell envelope. In contrast, E6 upregulates several genes, such as vimentin, that are usually expressed in mesenchymal lineages. E6 also modulates levels of genes involved in inflammation, including Cox-1 and Nag-1. By using E6 mutants that differentially target p53 for degradation, we determined that E6 regulates cellular genes by both p53-dependent and independent mechanisms. The microarray data also indicate that HPV-16 E6 modulates certain effects of HPV-16 E7 on cellular gene expression. The identification of E6-regulated genes in this analysis provides a basis for further studies on their role in HPV infection and cellular transformation.
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PMID:Microarray analysis identifies differentiation-associated genes regulated by human papillomavirus type 16 E6. 1451 73

The role of somatic mutation in cancer is well established and several genes have been identified that are frequent targets. This has enabled large-scale screening studies of the spectrum of somatic mutations in cancers of particular organs. Cancer gene mutation databases compile the results of many studies and can provide insight into the importance of specific amino acid sequences and functional domains in cancer, as well as elucidate aspects of the mutation process. Past studies of the spectrum of cancer mutations (in particular genes) have examined overall frequencies of mutation (at specific nucleotides) and of missense, nonsense, and silent substitution (at specific codons) both in the sequence as a whole and in a specific functional domain. Existing methods ignore features of the genetic code that allow some codons to mutate to missense, or stop, codons more readily than others (i.e., by one nucleotide change, vs. two or three). A new codon-based method to estimate the relative rate of substitution (fixation of a somatic mutation in a cancer cell lineage) of nonsense vs. missense mutations in different functional domains and in different tumor tissues is presented. Models that account for several potential influences on rates of somatic mutation and substitution in cancer progenitor cells and allow biases of mutation rates for particular dinucleotide sequences (CGs and dipyrimidines), transition vs. transversion bias, and variable rates of silent substitution across functional domains (useful in detecting investigator sampling bias) are considered. Likelihood-ratio tests are used to choose among models, using cancer gene mutation data. The method is applied to analyze published data on the spectrum of p53 mutations in cancers. A novel finding is that the ratio of the probability of nonsense to missense substitution is much lower in the DNA-binding and transactivation domains (ratios near 1) than in structural domains such as the linker, tetramerization (oligomerization), and proline-rich domains (ratios exceeding 100 in some tissues), implying that the specific amino acid sequence may be less critical in structural domains (e.g., amino acid changes less often lead to cancer). The transition vs. transversion bias and effect of CpG dinucleotides on mutation rates in p53 varied greatly across cancers of different organs, likely reflecting effects of different endogenous and exogenous factors influencing mutation in specific organs.
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PMID:Likelihood models of somatic mutation and codon substitution in cancer genes. 1457 81


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