Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the p53 tumor suppressor gene are the most frequent genetic alterations found in human cancers. Recent identification of two human homologues of p53 has raised the prospect of functional interactions between family members via a conserved oligomerization domain. Here we report in vitro and in vivo analysis of homo- and hetero-oligomerization of p53 and its homologues, p63 and p73. The oligomerization domains of p63 and p73 can independently fold into stable homotetramers, as previously observed for p53. However, the oligomerization domain of p53 does not associate with that of either p73 or p63, even when p53 is in 15-fold excess. On the other hand, the oligomerization domains of p63 and p73 are able to weakly associate with one another in vitro. In vivo co-transfection assays of the ability of p53 and its homologues to activate reporter genes showed that a DNA-binding mutant of p53 was not able to act in a dominant negative manner over wild-type p73 or p63 but that a p73 mutant could inhibit the activity of wild-type p63. These data suggest that mutant p53 in cancer cells will not interact with endogenous or exogenous p63 or p73 via their respective oligomerization domains. It also establishes that the multiple isoforms of p63 as well as those of p73 are capable of interacting via their common oligomerization domain.
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PMID:p73 and p63 are homotetramers capable of weak heterotypic interactions with each other but not with p53. 1037 84

The p53 protein is related by sequence homology and function to the products of two other genes, p63 and p73, that each encode several isoforms. We and others have discovered previously that certain tumor-derived mutants of p53 can associate and inhibit transcriptional activation by the alpha and beta isoforms of p73. In this study we have extended these observations to show that in transfected cells a number of mutant p53 proteins could bind and down-regulate several isoforms not only of p73 (p73 alpha, -beta, -gamma, and -delta) but also of p63 (p63 alpha and -gamma; Delta Np63 alpha and -gamma). Moreover, a correlation existed between the efficiency of p53 binding and the inhibition of p63 or p73 function. We also found that wild-type p63 and p73 interact efficiently with each other when coexpressed in mammalian cells. The interaction between p53 mutants and p63 or p73 was confirmed in a physiological setting by examining tumor cell lines that endogenously express these proteins. We also demonstrated that purified p53 and p73 proteins interact directly and that the p53 core domain, but not the tetramerization domain, mediates this interaction. Using a monoclonal antibody (PAb240) that recognizes an epitope within the core domain of a subset of p53 mutants, we found a correlation between the ability of p53 proteins to be immunoprecipitated by this antibody and their ability to interact with p73 or p63 in vitro and in transfected cells. Based on these results and those of others, we propose that interactions between the members of the p53 family are likely to be widespread and may account in some cases for the ability of tumor-derived p53 mutants to promote tumorigenesis.
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PMID:A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. 1123 24

The p53 tumor suppressor protein is mutated in more than 50% of all human cancers, which makes the study of its functions and activities critical for the understanding and management of cancer. In response to cellular stresses, p53 is activated and can mediate cell cycle arrest and/or apoptosis via the upregulation of numerous target genes. Here, we have identified EphA2 as a target gene of the p53 family, that is, p53, p73, and p63. We also found that an increase of EphA2 transcript levels correlated with an increase of EphA2 protein expression, and induction of EphA2 in response to DNA damage corresponded with p53 activation. Furthermore, we identified a p53 response element located within the EphA2 promoter that is responsive to wild-type p53, p73, and p63, but not mutant p53. Interestingly, the ligand for EphA2, ephrin-A1, is also regulated by p53. EphA2 and ephrin-A1 are members of the Eph family of receptor tyrosine kinases and ligands, which are implicated in a number of developmental processes. To analyse the role of EphA2 in p53-mediated tumor suppression, we generated stable cell lines capable of expressing exogenous EphA2 in a tetracycline-repressible system. We found that EphA2 expression resulted in an increase in apoptosis. Thus, we hypothesize that the activated EphA2 may serve to impair anti-apoptotic signaling, perhaps by disrupting focal adhesions and thereby sensitize cells to pro-apoptotic stimuli.
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PMID:Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. 1164 74

The p53 tumor suppressor gene is the most frequent target for genetic alterations in human cancers, whereas the recently discovered homologues p73 and p63 are rarely mutated. We and others have previously reported that human tumor-derived p53 mutants can engage in a physical association with different isoforms of p73, inhibiting their transcriptional activity. Here, we report that human tumor-derived p53 mutants can associate in vitro and in vivo with p63 through their respective core domains. We show that the interaction with mutant p53 impairs in vitro and in vivo sequence-specific DNA binding of p63 and consequently affects its transcriptional activity. We also report that in cells carrying endogenous mutant p53, such as T47D cells, p63 is unable to recruit some of its target gene promoters. Unlike wild-type p53, the binding to specific p53 mutants markedly counteracts p63-induced growth inhibition. This effect is, at least partially, mediated by the core domain of mutant p53. Thus, inactivation of p53 family members may contribute to the biological properties of specific p53 mutants in promoting tumorigenesis and in conferring selective survival advantage to cancer cells.
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PMID:Physical interaction with human tumor-derived p53 mutants inhibits p63 activities. 1189 50

p53 gene is a member of a multigene family that includes p53, p63 and p73. The association of p73 and p63 with cell transformation has been elusive as no genetic or epigenetic alteration of these genes has been uncovered yet. Recent work has shown clearly that p73 is an essential component of the signaling pathway that lead to apoptosis after DNA damage induced by cytotoxic agents use in cancer therapy. Furthermore, it has been established that a sub-category of mutant p53 is able to interact with p73 and inhibit its apoptotic activity. Such discovery will be important for a better understanding of the signaling pathway that lead to resistance to chemotherapy.
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PMID:[p53 mutations and resistance to chemotherapy: a stab in the back for p73?]. 1285 Jul 59

We recently showed that ASPP1 and ASPP2 stimulate the apoptotic function of p53. We show here that ASPP1 and ASPP2 also induce apoptosis independently of p53. By binding to p63 and p73 in vitro and in vivo, ASPP1 and ASPP2 stimulate the transactivation function of p63 and p73 on the promoters of Bax, PIG3, and PUMA but not mdm2 or p21(WAF-1/CIP1). The expression of ASPP1 and ASPP2 also enhances the apoptotic function of p63 and p73 by selectively inducing the expression of endogenous p53 target genes, such as PIG3 and PUMA, but not mdm2 or p21(WAF-1/CIP1). Removal of endogenous p63 or p73 with RNA interference demonstrated that (16) the p53-independent apoptotic function of ASPP1 and ASPP2 is mediated mainly by p63 and p73. Hence, ASPP1 and ASPP2 are the first two identified common activators of all p53 family members. All these results suggest that ASPP1 and ASPP2 could suppress tumor growth even in tumors expressing mutant p53.
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PMID:ASPP1 and ASPP2: common activators of p53 family members. 1472 77

The importance of p53 in chemotherapy-induced apoptosis of cancer cells is well established. p53 plays a critical role in the cellular response to DNA damage by regulating genes involved in cell cycle progression, apoptosis, and genomic stability. As a result, p53 tumor status is a critical determinant of both responses to anti-cancer treatment and clinical prognosis. Interestingly, tumors expressing certain mutant forms of p53 ("gain of function") are particularly resistant to chemotherapy, even when compared to cells that lack any detectable p53. Until recently, the explanation for this enhanced chemoresistance was not clear. Recent studies have shown that the p53 homologues, p73 and p63, are also activated by chemotherapies, leading to tumor cell death. Now the discovery that mutant p53 interacts with p73, and that regulation of this interaction by a p53 polymorphism can modulate chemosensitvity provide a new model for how p53-family interactions can influence the response of tumors to anti-cancer therapies. Since p53 mutations are found in more than 50% of human tumors, strategies aimed at manipulating these interactions may prove useful in enhancing the chemotherapy response, and perhaps, overcoming chemoresistance.
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PMID:Family feud in chemosensitvity: p73 and mutant p53. 1473 81

The tumor suppressor p53 is transcription factor composed of four identical subunits. The majority of the mutations in p53 are missense mutations that impair DNA binding. On the other hand, the p53-related p63 and p73 genes are rarely mutated, but many cell types express natural variants lacking the N-terminal transactivation domain (NDelta). Compelling evidence indicates that both the DNA binding-defective and NDelta mutants can impair the function of wild-type p53 in a dominant-negative manner. Interestingly, it is uncertain how many mutant subunit(s) a p53 tetramer can tolerate. In this study, we first made theoretical predictions based on the number of mutant p53 monomers needed to inactivate a tetramer and then tested how well the experimental data fit the predicted values. Surprisingly, these experiments reveal that DNA binding-defective p53 mutants (R249S and R273H) are very ineffective in impairing the transcriptional activity of p53: at least three mutants are required to inactivate a tetramer. In marked contrast, p53NDelta is a very potent inhibitor of p53: one NDelta subunit per tetramer is sufficient to abolish the transcriptional activity. DNA binding is not necessary for the NDelta proteins to inactivate p53. Similarly, NDelta variants of p63 and p73 are also powerful inhibitors of members of the p53 family. These results have important implications for our thinking about the mechanism of tumorigenesis involving missense p53 mutants or the N-terminally truncated isoforms.
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PMID:How many mutant p53 molecules are needed to inactivate a tetramer? 1506 Jan 72

The p53 tumor suppressor protein is a key mediator of an ATM-dependent DNA damage response cascade following cellular exposure to ionizing radiation. The p53-family members, p63 and p73, are highly similar to p53, yet are differentially activated by IR, UV and cis-platinum via ATM and c-abl/ATR signaling pathways. Loss of function of p53 can occur by mutation or degradation; giving rise to alterations in G(1) and G(2) cell cycle checkpoint control, cell death, DNA repair and genetic stability. The end result of these alterations can be the generation of radioresistant mutant tumor cells. Indeed, in isogenic systems, loss of p53 or p73 function has been associated with decreased chemosensitivity and radiosensitivity, in vitro. However, clinical data supporting a role for p53 genotype as an independent predictive factor for radiotherapy outcome continues to be controversial due to variable endpoints in clinical trial design and in methodology in detecting p53 function. Nonetheless, in carefully controlled radiotherapy studies where mutations in p53 have been detected using DNA sequencing or functional assays, the presence of mutant p53 can be associated with decreased local control following radiotherapy. This suggests that novel molecular treatment strategies specifically designed to re-institute normal p53 function within resistant tumors can be used as combined modality protocols to improve local control and maintain a therapeutic ratio. A future challenge lies in the pre-therapy determination of a 'molecular therapeutic ratio' for individual patients which could allow for specific prognostication based on p53 functional status and subsequent individualized therapy.
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PMID:The p53 protein family and radiation sensitivity: Yes or no? 1519 26

The p53 protein plays a major role in the maintenance of genome stability in mammalian cells. Mutations of p53 occur in over 50% of all cancers and are indicative of highly aggressive cancers that are hard to treat. Recently, there has been a high degree of interest in therapeutic approaches to restore growth suppression functions to mutant p53. Several compounds have been reported to restore wild type function to mutant p53. One such compound, CP-31398, has been shown effective in vivo, but questions have arisen to whether it actually affects p53. Here we show that mutant p53, isolated from cells treated with CP-31398, is capable of binding to p53 response elements in vitro. We also show the compound restores DNA-binding activity to mutant p53 in cells as determined by a chromatin immunoprecipitation assay. In addition, using purified p53 core domain from two different hotspot mutants (R273H and R249S), we show that CP-31398 can restore DNA-binding activity in a dose-dependent manner. Using a quantitative DNA binding assay, we also show that CP-31398 increases significantly the amount of mutant p53 that binds to cognate DNA (B(max)) and its affinity (K(d)) for DNA. The compound, however, does not affect the affinity (K(d) value) of wild type p53 for DNA and only increases B(max) slightly. In a similar assay PRIMA1 does not have any effect on p53 core DNA-binding activity. We also show that CP-31398 had no effect on the DNA-binding activity of p53 homologs p63 and p73.
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PMID:CP-31398 restores DNA-binding activity to mutant p53 in vitro but does not affect p53 homologs p63 and p73. 1530 39


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