Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human p300/CBP-associating factor, PCAF, mediates transcriptional activation through its ability to acetylate nucleosomal histone substrates as well as transcriptional activators such as p53. We have determined the 2.3 A crystal structure of the histone acetyltransferase (HAT) domain of PCAF bound to coenzyme A. The structure reveals a central protein core associated with coenzyme A binding and a pronounced cleft that sits over the protein core and is flanked on opposite sides by the N- and C-terminal protein segments. A correlation of the structure with the extensive mutagenesis data for PCAF and the homologous yeast GCN5 protein implicates the cleft and the N- and C-terminal protein segments as playing an important role in histone substrate binding, and a glutamate residue in the protein core as playing an essential catalytic role. A structural comparison with the coenzyme-bound forms of the related N-acetyltransferases, HAT1 (yeast histone acetyltransferase 1) and SmAAT (Serratia marcescens aminoglycoside 3-N-acetyltransferase), suggests the mode of substrate binding and catalysis by these enzymes and establishes a paradigm for understanding the structure-function relationships of other enzymes that acetylate histones and transcriptional regulators to promote activated transcription.
 ...
PMID:Crystal structure of the histone acetyltransferase domain of the human PCAF transcriptional regulator bound to coenzyme A. 1039 69

Nuclear receptors are ligand-dependent transcription factors which can also be activated in the absence of their lipophilic ligands by signaling substances acting on cell membrane receptors. This ligand-independent activation indicates the importance of nuclear receptor phosphorylation for their function. Nuclear receptor-mediated transcription of target genes is further increased by interactions with recruited coactivators forming a novel family of nuclear proteins. CBP/p300, a coactivator of different classes of transcription factors, including the tumor suppressor protein p53, plays a special role acting as a bridging protein between inducible transcription factors and the basal transcription apparatus, and as an integrator of diverse signaling pathways. Coactivators of nuclear receptors and associated proteins forming a multicomponent complex have an intrinsic histone acetylase activity in contrast to nuclear receptor and heterodimer Mad-Max corepressors, which recruit histone deacetylase. Similarly the Rb protein interacts with histone deacetylase to repress transcription of cell cycle regulatory genes. Targeted histone acetylation/deacetylation results in remodeling of chromatin structure and correlates with activation/repression of transcription. Recent data point to the important role of coactivator proteins associated with inducible transcription factors in transcription regulation, and in the integration of multiple signal transduction pathways within the nucleus.
 ...
PMID:Nuclear receptors, their coactivators and modulation of transcription. 1045 83

The retinoblastoma protein (pRB) can both positively and negatively regulate transcription. The former correlates with its ability to promote differentiation and the latter with its ability to regulate entry into S-phase. pRB negatively regulates transcription by forming complexes with members of the E2F transcription factor family. These complexes, when bound to E2F sites within certain target genes, actively repress transcription through a variety of mechanisms including physical interaction with adjacent transcriptional activation domains and recruitment of proteins that directly, or indirectly, lead to histone deacetylation. pRB function is, in turn, modulated by phosphorylation mediated by cyclin-dependent kinases. Emerging data suggest that combinatorial control of pRB function may be achieved through the use of different phosphoacceptor sites, different cyclin/cdk docking sites, and different cyclin/cdk complexes. The untimely activation of E2F responsive genes can induce apoptosis. This comes about at least partly through the induction of ARF, which leads to the stabilization and activation of p53. BioEssays 1999;21:950-958.
 ...
PMID:Functions of the retinoblastoma protein. 1051 68

There is growing evidence that the p53 tumor suppressor protein not only can function to activate gene transcription but also to repress the expression of specific genes. Although recent studies have implicated the transcriptional repression function of p53 in the pathway of apoptosis, the molecular basis of this activity remains poorly understood. This study takes a first step toward elucidating this mechanism. We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin. Consistent with this finding, we report that p53 physically associates in vivo with HDACs. This interaction is not direct but, rather, is mediated by the corepressor mSin3a. Both wild-type p53 and mSin3a, but not mutant p53, can be found bound to the Map4 promoter at times when this promoter preferentially associates with deacetylated histones in vivo. Significantly, inhibition of p53-mediated transcriptional repression with TSA markedly inhibits apoptosis induction by p53. These data offer the first mechanistic insights for p53-mediated transcriptional repression and underscore the importance of this activity for apoptosis induction by this protein.
 ...
PMID:Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. 1052 94

We have reported that histone acetylation induced by trichostatin A (TSA) promotes p21(waf1/cip1) (p21) expression, the GC-box located just upstream of TATA box was responsible for TSA-induced promoter activation, and both Sp1 and Sp3 were the working activator of this GC-box. To understand the molecular pathway from histone acetylation to this Sp1 family factors-mediated promoter activation, we investigated the function of p300, one of the histone acetyltransferase, in the present work. The evidence supporting the linkage between p300 and TSA-induced p21 promoter activation were realized from the following findings: 1) cotransfection of p300 elevated p21 promoter activity, and this elevation was dependent on TSA-responsive GC-box; 2) TSA-induced promoter activation was blocked by the introduction of p300 dominant-negative mutant into cells; and 3) Sp1- or Sp3-mediated activation was also suppressed by this p300 dominant-negative mutant. Our data also suggested that p300 collaborates with Sp1 in a way which is different from that when p300 collaborates with p53 in p21 transcription.
 ...
PMID:p300 collaborates with Sp1 and Sp3 in p21(waf1/cip1) promoter activation induced by histone deacetylase inhibitor. 1062 87

Trichostatin A (TSA), an inhibitor of the eukaryotic cell cycle and an inducer of morphological reversion of transformed cells, inhibits histone deacetylase (HDAC) at nanomolar concentrations. Recently, trapoxin, oxamflatin, and FR901228, antitumor agents structurally unrelated to TSA, were found to be potent HDAC inhibitors. These inhibitors activate expression of p21Waf1 and 16INK4A in a p53-independent manner. Changes in the expression of these cell cycle regulators by an increase in histone acetylation may be responsible for cell cycle arrest and antitumor activity by HDAC inhibitors. The target molecule of leptomycin B (LMB), a potent antitumor agent, was genetically and biochemically identified as CRM1, a protein reported as being required for chromosome structure control. We showed that CRM1 was a receptor for the nuclear export signal (NES) and that LMB inhibited nuclear export of proteins. Using LMB, we identified a novel NES in fission yeast transcription factor Pap1, the function of which is abolished by oxidative stress in a manner conserved in eukaryotes.
 ...
PMID:Trichostatin and leptomycin. Inhibition of histone deacetylation and signal-dependent nuclear export. 1066

Trichostatin A (TSA), a specific histone deacetylase inhibitor, induces histone hyperacetylation and modulates the expression of some genes. We examined the effects of TSA on MG63 cells. TSA induced growth arrest and expression of the p21/WAF1/Cip1 protein. A close correlation between the level of histone acetylation and induction of the p21/WAF1/Cip1 protein was detected. Using several mutant p21/WAF1/Cip1 promoter fragments, mutation of either of two Sp1 sites at -82 or -69 of the p21/WAF1/Cip1 promoter reduced the responsiveness to TSA. This finding indicates that TSA activates the p21/WAF1/Cip1 promoter through the Sp1 sites in a p53-independent manner.
 ...
PMID:Histone deacetylase inhibitor activates the p21/WAF1/Cip1 gene promoter through the Sp1 sites. 1066 18

p53, the most commonly mutated gene in cancer cells, directs cell cycle arrest or induces programmed cell death (apoptosis) in response to stress. It has been demonstrated that p53 activity is up-regulated in part by posttranslational acetylation. In agreement with these observations, here we show that mammalian histone deacetylase (HDAC)-1, -2, and -3 are all capable of down-regulating p53 function. Down-regulation of p53 activity by HDACs is HDAC dosage-dependent, requires the deacetylase activity of HDACs, and depends on the region of p53 that is acetylated by p300/CREB-binding protein (CBP). These results suggest that interactions of p53 and HDACs likely result in p53 deacetylation, thereby reducing its transcriptional activity. In support of this idea, GST pull-down and immunoprecipitation assays show that p53 interacts with HDAC1 both in vitro and in vivo. Furthermore, a pre-acetylated p53 peptide was significantly deacetylated by immunoprecipitated wild type HDAC1 but not deacetylase mutant. Also, co-expression of HDAC1 greatly reduced the in vivo acetylation level of p53. Finally, we report that the activation potential of p53 on the BAX promoter, a natural p53-responsive system, is reduced in the presence of HDACs. Taken together, our findings indicate that deacetylation of p53 by histone deacetylases is likely to be part of the mechanisms that control the physiological activity of p53.
 ...
PMID:Histone deacetylases specifically down-regulate p53-dependent gene activation. 1077 77

The state of chromatin (the packaging of DNA in eukaryotes) has long been recognized to have major effects on levels of gene expression, and numerous chromatin-altering strategies-including ATP-dependent remodeling and histone modification-are employed in the cell to bring about transcriptional regulation. Of these, histone acetylation is one of the best characterized, as recent years have seen the identification and further study of many histone acetyltransferase (HAT) proteins and their associated complexes. Interestingly, most of these proteins were previously shown to have coactivator or other transcription-related functions. Confirmed and putative HAT proteins have been identified from various organisms from yeast to humans, and they include Gcn5-related N-acetyltransferase (GNAT) superfamily members Gcn5, PCAF, Elp3, Hpa2, and Hat1: MYST proteins Sas2, Sas3, Esa1, MOF, Tip60, MOZ, MORF, and HBO1; global coactivators p300 and CREB-binding protein; nuclear receptor coactivators SRC-1, ACTR, and TIF2; TATA-binding protein-associated factor TAF(II)250 and its homologs; and subunits of RNA polymerase III general factor TFIIIC. The acetylation and transcriptional functions of these HATs and the native complexes containing them (such as yeast SAGA, NuA4, and possibly analogous human complexes) are discussed. In addition, some of these HATs are also known to modify certain nonhistone transcription-related proteins, including high-mobility-group chromatin proteins, activators such as p53, coactivators, and general factors. Thus, we also detail these known factor acetyltransferase (FAT) substrates and the demonstrated or potential roles of their acetylation in transcriptional processes.
 ...
PMID:Acetylation of histones and transcription-related factors. 1083 22

The adenovirus E1B-55K protein is a multifunctional phosphoprotein that regulates nuclear to cytoplasmic export of host cell and viral mRNAs during lytic viral growth. E1B-55K also blocks apoptosis by binding and functionally inactivating the human tumor suppressor protein p53. Here, we show that E1B-55K interacts with histone deacetylase 1 (HDAC1) and the transcriptional corepressor protein mSin3A, both in the adenovirus-transformed 293 cell line and during a lytic adenovirus infection. Furthermore, we show that the central amino acids 156-261 in E1B-55K are necessary for efficient HDAC1 interaction. Importantly, the E1B-55K/mSin3A/HDAC1 complex is also enzymatically active, catalyzing deacetylation of a histone substrate peptide. Collectively, our results suggest that E1B-55K interaction with mSin3A/HDAC1 containing complexes may be significant for one or several of the multiple activities ascribed to this protein.
 ...
PMID:The adenovirus-2 E1B-55K protein interacts with a mSin3A/histone deacetylase 1 complex. 1091 22


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>