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)

Coactivators such as cyclic AMP-response-element binding protein (CREB)-binding protein (CBP) and p300/CBP associated factor (P/CAF) play a crucial role in coordinating and cointegrating eukaryotic transcription. One of the recent paradigms in the eukaryotic transcription field is the finding of molecular basis of coactivator function. The well characterized coactivators such as CBP and P/CAF have been proposed to coactivate/cointegrate gene expression with many transcription activators through two mechanisms. One is complex formation with the components with basal transcriptional machinery. Another is its intrinsic and associated enzymatic activity, which transfers an acetyl-base to the epsilon ( epsilon ) portion of lysine-residues in histones and certain nuclear proteins (factor acetyltransferases; FATs), such as p53, lymphoid enhancer-binding factor (LEF), and transcription factor IIE (TFIIE), which often results in increased transcriptional activity. Recently, the status of hyper nuclear acetylation (HNA) has been thought to influence proliferation, differentiation and apoptosis. Furthermore, recent reports showed that histone acetyltransferase (HAT) activity is increased in human disease, such as cancer and atherosclerosis, and studies have shown associations between nuclear acetylation/deacetylation and cell proliferation/differentiation.
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PMID:Hyper nuclear acetylation (HNA) in proliferation, differentiation and apoptosis. 1272 76

The tumor suppressor protein PML and oncoprotein MDM2 have opposing effects on p53. PML stimulates p53 activity by recruiting it to nuclear foci termed PML nuclear bodies. In contrast, MDM2 inhibits p53 by promoting its degradation. To date, neither a physical nor functional relationship between PML and MDM2 has been described. In this study, we report an in vivo and in vitro interaction between PML and MDM2 which is independent of p53. Two separate regions of PML are recognized which can interact with MDM2. The C-terminal half of PML, encoded by residues 300-633, can interact with the central region of MDM2 which includes the MDM2 acidic domain. In addition, PML amino acids 1-200, which encode the RING-finger and most of the B box zinc binding motifs, can interact with the C-terminal, RING-finger containing region of MDM2. Interestingly, PML mutants in which sumoylation at lysine 160 was inhibited displayed an increased association with MDM2, suggesting that sumoylation at this site may be a determinant of PML-MDM2 binding. Coexpression with MDM2 caused a redistribution of PML from the nucleus to the cytoplasm, and this required the PML N terminus and the MDM2 RING-finger domain. These results suggest that interaction between the PML N terminus and MDM2 C terminus can promote PML nuclear exclusion. Wild-type MDM2 inhibited the ability of PML to stimulate the transcriptional activity of a GAL4-CBP fusion protein. This inhibition required the central, acidic region of MDM2, but did not require the MDM2 C terminus. Taken together, these studies demonstrate that MDM2 and PML can interact through at least two separate protein regions, and that these interactions can have specific effects on the activity and/or localization of PML.
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PMID:Physical and functional interactions between PML and MDM2. 1275 44

P2P-R is the alternately spliced product of the P2P-R/PACT gene in that P2P-R lacks one exon encoding 34 amino acids. The 250 kDa P2P-R protein is the predominate product expressed in multiple murine cell lines. It is a highly basic protein that contains multiple domains including an N-terminal RING type zinc finger, a proline rich domain, an RS region, and a C-terminal lysine-rich domain. P2P-R binds the p53 and the Rb1 tumor suppressors and is phosphorylated by the cdc2 and SRPK1a protein kinases. P2P-R also interacts with scaffold attachment factor-B (SAF-B), a well characterized MARs (for matrix attachment regions) binding factor, and may interact with nucleolin, another MARs binding factor. In addition, P2P-R binds single strand DNA (ssDNA). The expression of P2P-R is regulated by differentiation and cell cycle events. P2P-R mRNA is markedly repressed during differentiation, whereas immunoreactive P2P-R protein levels are >10-fold higher in mitotic than in G(0) cells. The localization of P2P-R also is modulated during the cell cycle. During interphase, P2P-R is present primarily in nucleoli and nuclear speckles whereas during mitosis, P2P-R associates with the periphery of chromosomes. Overexpression of near full length P2P-R induces mitotic arrest in prometaphase and mitotic apoptosis, and overexpression of selected P2P-R segments also can promote apoptosis. This compendium of data supports the possibility that P2P-R may form complexes with the Rb1 and/or p53 tumor suppressors and MARs-related factors, in a cell cycle and cell differentiation-dependent manner, to influence gene transcription/expression and nuclear organization.
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PMID:Functional potential of P2P-R: a role in the cell cycle and cell differentiation related to its interactions with proteins that bind to matrix associated regions of DNA? 1293 51

The effect of different regimes of lysine-pre treatment on mutation at the 3rd nucleotide base of codon 249 which is located at the 7th exon of p53 gene of Chang-liver cells (CCIL13) exposed to aflatoxin B1 (AFB1) has been investigated. There is an indication of inhibition of 1 ug/ml AFB1--induced mutation by pretreatment of cells for 72 hr with 5-molar fold lysine equivalent of 1 ug/ml AFB1 1 u/g ml AFB1 was the does at which there was 50% survival among the cells of CC13 in cytotoxicity studies. The results suggest chemo prevention of AFB1 induced mutation at codon 249 locus of Exon 7 in CCL13's p53 gene and by implication, maybe, AFB1-induced primary liver cancer.
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PMID:P53 gene of chang-liver cells (Atcc-Ccl13) exposed to aflatoxin B1 (Afb): the effect of lysine on mutation at codon 249 of exon 7. 1295 91

Over the past years, modification by covalent attachment of SUMO (small ubiquitin-like modifier) has been demonstrated for of a number of cellular and viral proteins. While increasing evidence suggests a role for SUMO modification in the regulation of protein-protein interactions and/or subcellular localization, most SUMO targets are still at large. In this report we show that Topors, a Topoisomerase I and p53 interacting protein of hitherto unknown function, presents a novel cellular target for SUMO-1 modification. In a yeast two-hybrid system, Topors interacted with both SUMO-1 and the SUMO-1 conjugating enzyme UBC9. Multiple SUMO-1 modified forms of Topors could be detected after cotransfection of exogenous SUMO-1 and Topors induced the colocalization of a YFP tagged SUMO-1 protein in a speckled pattern in the nucleus. A subset of these Topors' nuclear speckles were closely associated with the PML nuclear bodies (POD, ND10). A central domain comprising Topors residues 437 to 574 was sufficient for both sumolation and localization to nuclear speckles. One SUMO-1 acceptor site at lysine residue 560 could be identified within this region. However, sumolation-deficient Topors mutants showed that sumolation obviously is not required for localization to nuclear speckles.
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PMID:The DNA topoisomerase I binding protein topors as a novel cellular target for SUMO-1 modification: characterization of domains necessary for subcellular localization and sumolation. 1451 84

Histone modification enables the ordered regulation of DNA-related processes. Here, we ask if p53, which interacts with histone modifying complexes in vivo, influences histone H3 modification. For this purpose, we compared isogenic clones of human p53+/+ and p53-/- cells in which it is reasonable to attribute any observed differences in histone modification to p53-related effects. Cell growth and cell cycle analyses indicated equivalent proliferation rates for the p53+/+ and p53-/- cell clones. Modification of histone H3 was determined under normal cell growth conditions and also after UV irradiation and/or treatment with trichostatin A (TSA) or nicotinamide (two inhibitors of histone deacetylation). Site-specific histone H3 modifications were determined by immunoblotting. We provide evidence that p53 influences histone H3 acetylation at lysine 9 (K9) and K14, whereas acetylation of K18 appears to be p53 independent. The most striking p53-related effects are at K9, which is underacetylated in p53-/- cells under normal conditions of growth but which shows a dramatic increase in acetylation after combined treatment with UV plus TSA. Conversely, phosphorylation of serine 10 (S10P) is elevated in p53-/- cells and reduced after UV plus TSA treatment. Similar reciprocity between K9Ac and S10P was not evident in p53+/+ cells. Abnormal S10P in p53-/- cells was also observed under completely different experimental conditions where cells were treated with nocodazole to induce G(2)-M arrest and elevation of S10P (which is linked with G(2)-M of the cell cycle). On removal of nocodazole, the p53+/+ cells exhibited rapid reduction in S10P levels and cell cycle recovery. In contrast, the p53-/- cells retained elevated S10P levels and failed to show normal cell cycle recovery. Phosphorylation of S10 is known to be linked with the initiation of chromosome condensation in G(2) and is also important for proper chromosome segregation at mitosis. Our results indicate that loss of p53, directly or indirectly, perturbs the normal regulation of S10 phosphorylation. We suggest that this effect may contribute toward the development of abnormal chromosomes and aneuploidy in p53-deficient cancers.
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PMID:Loss of p53 has site-specific effects on histone H3 modification, including serine 10 phosphorylation important for maintenance of ploidy. 1458 61

Compared to proliferating keratinocytes (KCs), growth-arrested KCs are relatively resistant to UV-light induced apoptosis. When KCs undergo confluency, or following exposure to anti-proliferative agents such as IFN-gamma plus a phorbol ester-12-O-tetradecanoylyphorbol-13-acetate (TPA), they convert from a proliferative to a nonproliferative state resembling senescence. Since p53 regulates UV-induced apoptosis of KCs, this report further characterizes p53 half-life, post-translational modifications, and transcriptional activity using cultured human KCs and living epidermal equivalents. The half-life of p53 in KCs was longer than fibroblasts (greater than approximately 3 h vs. 30 min). Exposure of proliferating KCs to UV-light induces post-translational modifications of p53 including acetylation of lysine-382 residues. By contrast, KCs undergoing irreversible growth arrest following confluency, or exposure to IFN-gamma plus TPA, were resistant to UV-induced apoptosis, and failed to undergo the acetylation modification of p53. Exposure of KCs to IFN-gamma plus TPA reduced total cellular p53 levels and reduced the transcriptional activity of p53. Addition of Trichostatin A (TSA), an inhibitor of de-acetylation, increased acetylation of lysine-382 in confluent KCs, thereby enhancing susceptibility of confluent cultures to UV-induced apoptosis. Pre-treatment of epidermal equivalents with IFN-gamma plus TPA also blocked UV-light induced increase in p53 levels, and reduced apoptosis. In conclusion, these studies demonstrate that growth arrested KCs may resist UV-light induced apoptosis by inactivating the pro-apoptotic function of p53.
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PMID:Resistance to UV-induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53. 1458 49

We recently showed that alpha4beta1 integrin induces B-cell chronic lymphocytic leukemia (B-CLL) cell resistance to fludarabine-induced apoptosis via upregulation of Bcl-xL. We have now studied whether p53 was involved in this response. Cells from five B-CLL patients with wild-type p53 determined by DNA sequencing, or from the EHEB cell line, cultured on the alpha4beta1 ligand H/89 during fludarabine treatment, showed significantly higher viability (P<or=0.001) than cells cultured on poly-D-lysine (pLys). Parallel to this different viability, fludarabine increased p53 expression on pLys-cultured cells and this increase was significantly reduced (P<or=0.05) on cells cultured on H/89. Thus, p53 appears to be part of the survival pathway induced by alpha4beta1 ligation and may contribute to the progressive drug resistance in B-CLL.
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PMID:Involvement of p53 in alpha4beta1 integrin-mediated resistance of B-CLL cells to fludarabine. 1462 30

The CDK inhibitor p21waf1/cip1 is degraded by a ubiquitin-independent proteolytic pathway. Here, we show that MDM2 mediates this degradation process. Overexpression of wild-type or ring finger-deleted, but not nuclear localization signal (NLS)-deleted, MDM2 decreased p21waf1/cip1 levels without ubiquitylating this protein and affecting its mRNA level in p53(-/-) cells. This decrease was reversed by the proteasome inhibitors MG132 and lactacystin, by p19(arf), and by small interfering RNA (siRNA) against MDM2. p21waf1/cip1 bound to MDM2 in vitro and in cells. The p21waf1/cip1-binding-defective mutant of MDM2 was unable to degrade p21waf1/cip1. MDM2 shortened the half-life of both exogenous and endogenous p21waf1/cip1 by 50% and led to the degradation of its lysine-free mutant. Consequently, MDM2 suppressed p21waf1/cip1-induced cell growth arrest of human p53(-/-) and p53(-/-)/Rb(-/-)cells. These results demonstrate that MDM2 directly inhibits p21waf1/cip1 function by reducing p21waf1/cip1 stability in a ubiquitin-independent fashion.
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PMID:MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. 1463 95

Histone acetyltransferase (HAT) proteins often exhibit a high degree of specificity for lysine-bearing protein substrates. We have previously reported on the structure of the Tetrahymena Gcn5 HAT protein (tGcn5) bound to its preferred histone H3 substrate, revealing the mode of substrate binding by the Gcn5/PCAF family of HAT proteins. Interestingly, the Gcn5/PCAF HAT family has a remarkable ability to acetylate lysine residues within diverse cognate sites such as those found around lysines 14, 8, and 320 of histones H3, H4, and p53, respectively. To investigate the molecular basis for this, we now report on the crystal structures of tGcn5 bound to 19-residue histone H4 and p53 peptides. A comparison of these structures with tGcn5 bound to histone H3 reveals that the Gcn5/PCAF HATs can accommodate divergent substrates by utilizing analogous interactions with the lysine target and two C-terminal residues with a related chemical nature, suggesting that these interactions play a general role in Gcn5/PCAF substrate binding selectivity. In contrast, while the histone H3 complex shows extensive interactions with tGcn5 and peptide residues N-terminal to the target lysine, the corresponding residues in histone H4 and p53 are disordered, suggesting that the N-terminal substrate region plays an important role in the enhanced affinity of the Gcn5/PCAF HAT proteins for histone H3. Together, these studies provide a framework for understanding the substrate selectivity of HAT proteins.
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PMID:Molecular basis for Gcn5/PCAF histone acetyltransferase selectivity for histone and nonhistone substrates. 1466 47


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