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)

HDM2 is a negative regulator of p53 that inhibits its transcriptional activity and subjects it to degradation by an E3 ligase activity. The primary binding site for HDM2 on p53 is located in its N-terminal domain. A second site on the p53 core domain (p53C) binds to an unidentified site in HDM2. We found that this site is in its acidic domain and part of the zinc finger domain by examining the interaction of full-length and domain constructs of p53 with the N-terminal region of HDM2 and peptide arrays derived from the full-length protein. NMR spectroscopy showed that peptides derived from this region of HDM2 bound to residues in the specific DNA-binding site of p53C. The peptides were displaced from the site by gadd45 sequence-specific DNA. Phosphorylation of single amino acids in the central domain of HDM2 did not abolish the interaction between the HDM2-derived peptides and p53C. We speculate that this second binding site helps in stabilizing the interaction between HDM2 and p53 during p53 degradation.
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PMID:The central region of HDM2 provides a second binding site for p53. 1643 96

Common cancer mutations of p53 tend either to lower the stability or distort the core domain of the protein or weaken its DNA binding affinity. We have previously analyzed in vitro the effects of mutations on the core domain of p53. Here, we extend those measurements to full-length p53, using either the wild-type protein or a biologically active superstable construct that is more amenable to accurate biophysical measurements to assess the possibilities of rescuing different types of mutations by anticancer drugs. The tetrameric full-length proteins had similar apparent melting temperatures to those of the individual domains, and the structural mutations lowered the melting temperature by similar amounts. The thermodynamic stability of tetrameric p53 is thus dictated by its core domain. We determined that the common contact mutation R273H weakened binding to the gadd45 recognition sequence by approximately 700-1000 times. Many mutants that have lowered melting temperatures should be good drug targets, although the common R273H mutant binds response elements too weakly for simple rescue.
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PMID:Effects of common cancer mutations on stability and DNA binding of full-length p53 compared with isolated core domains. 1675 63

Tumour-derived p53 mutants are thought to have acquired 'gain-of-function' properties that contribute to oncogenicity. We have tested the hypothesis that p53 mutants suppress p53-target gene expression, leading to enhanced cellular growth. Silencing of mutant p53 expression in several human cell lines was found to lead to the upregulation of wild-type p53-target genes such as p21, gadd45, PERP and PTEN. The expression of these genes was also suppressed in H1299-based isogenic cell lines expressing various hot-spot p53 mutants, and silencing of mutant p53, but not TAp73, abrogated the suppression. Consistently, these hot-spot p53 mutants were able to suppress a variety of p53-target gene promoters. Analysis using the proto-type p21 promoter construct indicated that the p53-binding sites are dispensable for mutant p53-mediated suppression. However, treatment with the histone deacetylase inhibitor trichostatin-A resulted in relief of mutant p53-mediated suppression, suggesting that mutant p53 may induce hypo-acetylation of target gene promoters leading to the suppressive effects. Finally, we show that stable down-regulation of mutant p53 expression resulted in reduced cellular colony growth in human cancer cells, which was found to be due to the induction of apoptosis. Together, the results demonstrate another mechanism through which p53 mutants could promote cellular growth.
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PMID:Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gain of function of mutant p53. 1734 17

p53 is an important regulator of cell growth and apoptosis and its activity is regulated by phosphorylation. Accordingly, in neonatal rat cardiomyocytes we examined the involvement of p53 in H(2)O(2)-induced apoptosis. Treatment with 50-100 microM H(2)O(2) markedly induced apoptosis in cardiomyocytes, as assessed by gel electrophoresis of genomic DNA. To examine whether H(2)O(2) increases p53 phosphorylation in cardiomyocytes, we utilized an antibody that specifically recognizes phosphorylated p53 at serine-15. The level of phosphorylated p53 was markedly increased by 100 microM H(2)O(2) at 30 and 60 min. Using specific protein kinase inhibitors we examined the involvement of protein kinases in p53 phosphorylation in response to H(2)O(2) treatment. However, staurosporine, a broad spectrum inhibitor of protein kinases, SB202190, a specific p38 kinase inhibitor, PD98059, a MAP kinase inhibitor, wortmannin, an inhibitor of DNA-PK and PI3 kinase, SP600125, a JNK inhibitor and caffeine,an inhibitor of ATM and ATR, failed to prevent the H(2)O(2)-induced phosphorylation of p53. cDNA microarray revealed that H(2)O(2) markedly increased expression of several p53 upstream modifiers such as the p300 coactivator protein and several downstream effectors such as gadd45, but decreased the expression of MDM2, a negative regulator of p53. Our results suggest that phosphorylation of p53 at serine-15 may be an important signaling event in the H(2)O(2)-mediated apoptotic process.
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PMID:Oxidative stress enhances phosphorylation of p53 in neonatal rat cardiomyocytes. 1745 21

Immunohistochemical techniques were used to investigate the origin of a spindle cell tumor in the anterior uveal tract of dogs and the influence of ultraviolet radiation on the development of this tumor. Thirteen tumors were identified from the 4,007 canine ocular samples examined at the Comparative Ocular Pathology Laboratory of Wisconsin between 1978 and 2005. Siberian Husky and Siberian Husky mix dogs were overrepresented (10/13 dogs, overall median age 10 years). Light microscopic evaluation (all dogs) and electron microscopy (2 dogs) were performed. Immunohistochemical staining included alpha-smooth muscle actin (SMA), vimentin, S-100, desmin, glial fibrillary acidic protein (GFAP), Melan A, microphthalmic transcription factor (MITF-1), protein gene product 9.5 (PGP 9.5), laminin, gadd45, p53, proliferating cell nuclear antigen (PCNA), anti-UVssDNA (antibody for detection of (6-4)-dipyrimidine photoproducts), and telomerase reverse transcriptase (TERT). All tumors occurred in the iris with or without ciliary body involvement and were composed of spindle cells arranged in fascicles and whorls (variable Antoni A and B behavior). All tumors were positive when immunostained for vimentin and S-100. Nine of 13 tumors exhibited GFAP immunopositivity. All tumors were negative for SMA, desmin, Melan A, and MITF-1. Tumors were variably positive for PGP 9.5, laminin, gadd45, p53, PCNA, anti-UVssDNA, and TERT. Electron microscopy revealed intermittent basal laminae between cells. These tumors are morphologically and immunohistochemically most consistent with schwannoma. The relationship between spindle cell tumors of the anterior uvea of dogs, altered neural crest, blue iris color, and ultraviolet radiation has not yet been fully elucidated.
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PMID:Uveal spindle cell tumor of blue-eyed dogs: an immunohistochemical study. 1749 Oct 68

Hypoxia is a common feature of solid tumors and promotes resistance to apoptosis from cancer therapies that induce DNA damage. The mechanism for this resistance, however, remains unclear. Since activation of the p53 pathway plays a major role in determining whether cells undergo apoptosis in response to DNA damage, we performed a microarray analysis of p53-dependent gene expression changes in response to DNA damage combined with hypoxia. When the H460 human lung cancer cell line was treated with hypoxia and etoposide, a chemotherapy agent that induces double-stranded DNA breaks, the dominant transcriptional response was regulated by DNA damage in a p53-dependent manner. Interestingly, however, DNA damage combined with hypoxia modulated both the intensity of the p53 response and the composition of downstream target genes. For example, there was synergistic activation of known p53 target genes such as p21 and gadd45, and the unique induction of other potentially novel p53 target genes including Rad and I-Rel. In addition, analysis of repressed genes supported a model for antagonism of c-Myc signaling in hypoxia, based on the downregulation of several known c-Myc target genes and the induction of Mxi1, a c-Myc antagonist. These data suggest a hypothesis that the combination of hypoxia and DNA damage promotes resistance to therapy by eliciting a transcriptional response that favors cell cycle arrest over apoptosis.
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PMID:Microarray analysis of p53-dependent gene expression in response to hypoxia and DNA damage. 1808 15

The p53 protein family is involved in the control of an intricate network of genes implicated in cell cycle, through to germ line integrity and development. Although the role of p53 is well-established, the intrinsic nature of its homologue p73 has yet to be fully elucidated. Here, the biochemical characterization and homology-based modeling of the p73 protein is presented and the implications for its function(s) examined. The DNA binding domains (DBDs) of p53, p63, and p73 bind to the specific target site of a 30-mer gadd45 dsDNA, as tested by EMSA. The monomeric DBDs bind cooperatively forming tetrameric complexes. However, a larger construct consisting of p73 DBD plus TET domain (p73 CT) and the corresponding p53 DBD plus TET domain (p53 CT) bind gadd45 differently than the respective DBDs. Significantly, p73 DBD exhibited enhanced thermodynamic stability relative to the p53 DBD but not compared to p63 DBD as shown by DSC, CD, and equilibrium unfolding. The p73 CT is less stable than p73 DBD. The modeling data show distinct electrostatic surfaces of p73 and p53 dimers when bound to DNA. Specifically, the p73 surface is less complementary for DNA binding, which may account for the differences in affinity and specificity for p53 REs. These stability and DNA binding data for p73 in vitro enhance and complement our understanding of the role of the p73 protein in vivo and could be exploited in designing strategies for cancer therapy in places where p53 is mutated.
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PMID:The p73 DNA binding domain displays enhanced stability relative to its homologue, the tumor suppressor p53, and exhibits cooperative DNA binding. 1826 Jun 40

SETD2 (SET domain containing protein 2) is a histone H3K36 trimethyltransferase protein that associates with hyperphosphorylated RNA polymerase II and involves in transcriptional elongation. However, whether and how SETD2 is implicated in the specific regulation of gene transcription remains unknown. Here we show that SETD2 could interact with p53 and selectively regulate the transcription factor activity of p53. The interaction was dependent of C-terminal region of SETD2, which contains the SET and WW domains, and the N-terminal transactivation domain (residues 1-45) of p53. Overexpression of SETD2 upregulated the expression levels of a subset of p53 targets including puma, noxa, p53AIP1, fas, p21, tsp1, huntingtin, but downregulated that of hdm2. In contrast, it had no significant effect on those of 14-3-3sigma, gadd45 and pig3. Consistently, knockdown of endogenous SETD2 expression by RNA interference resulted in converse effects as expected. In p53-deficient H1299 cells, SETD2 lost the ability to regulate these gene expression except hdm2, indicating the dependence of p53. Furthermore, we demonstrated that SETD2 downregulated hdm2 expression by targeting its P2 promoter and then enhanced p53 protein stability. Collectively, these findings suggest that the histone methyltransferase SETD2 could selectively regulate the transcription of subset genes via cooperation with the transcription factor p53.
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PMID:Histone methyltransferase protein SETD2 interacts with p53 and selectively regulates its downstream genes. 1858 4

To assess the potential of mutations from the L1 loop of the tumour suppressor p53 as second-site suppressors, the effect of H115N and S116M on the p53 'hot spot' mutations has been investigated using the double-mutant approach. The effects of these two mutants on the p53 hot spots in terms of thermal stability and DNA binding were evaluated. The results show that: (i) the p53 mutants H115N and S116M are thermally more stable than wild-type p53; (ii) H115N but not S116M is capable of rescuing the DNA binding of one of the most frequent p53 mutants in cancer, R248Q, as shown by binding of R248Q/H115N to gadd45 (the promoter of a gene involved in cell-cycle arrest); (iii) the double mutant R248Q/H115N is more stable than wild-type p53; (iv) the effect of H115N as a second-site suppressor to restore DNA-binding activity is specific to R248Q, but not to R248W; (v) molecular-dynamics simulations indicate that R248Q/H115N has a conformation similar to wild-type p53, which is distinct from that of R248Q. These findings could be exploited in designing strategies for cancer therapy to identify molecules that could mimic the effect of H115N in restoring function to oncogenic p53 mutants.
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PMID:Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights. 2011 12

Previously, we defined SCY1-like 1 binding protein 1 (SCYL1-BP1) to be a substrate of Pirh2 that binds to mouse double minute gene number 2 (MDM2). In the current study, we found that an increase in SCYL1-BP1 protein levels caused a parallel change in the amount of p53 protein due to the inhibition by SCYL-BP1 of MDM2-mediated p53 ubiquitination. SCYL1-BP1 was not able to alter the ubiquitination of p53 by human papillomavirus protein E6, indicating that the effect was specific for MDM2. Increases in the level of SCYL1-BP1 protein in cells led to the greater transcriptional activation of p21 and gadd45, reduced rate of cellular proliferation, increased levels of apoptosis and inhibition of tumorigenicity. Thus, we propose that SCYL1-BP1 is a novel regulator of the MDM2-p53 feedback loop and that it may be a potential tumor suppressor.
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PMID:Overexpression of SCYL1-BP1 stabilizes functional p53 by suppressing MDM2-mediated ubiquitination. 2084 54


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