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 tumor suppressor p53 is stabilized and activated in response to cellular stress through post-translational modifications including acetylation. p300/CBP-mediated acetylation of p53 is negatively regulated by MDM2. Here we show that MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1. The HDAC1 complex binds MDM2 in a p53-independent manner and deacetylates p53 at all known acetylated lysines in vivo. Ectopic expression of a dominant-negative HDAC1 mutant restores p53 acetylation in the presence of MDM2, whereas wild-type HDAC1 and MDM2 deacetylate p53 synergistically. Fibroblasts overexpressing a dominant negative HDAC1 mutant display enhanced DNA damage-induced p53 acetylation, increased levels of p53 and a more pronounced induction of p21 and MDM2. These results indicate that acetylation promotes p53 stability and function. As the acetylated p53 lysine residues overlap with those that are ubiquitylated, our results suggest that one major function of p53 acetylation is to promote p53 stability by preventing MDM2-dependent ubiquitylation, while recruitment of HDAC1 by MDM2 promotes p53 degradation by removing these acetyl groups.
 ...
PMID:MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. 1242 95

CBP is a multifunctional transcriptional cofactor with tumor suppressor activity. The CH3 domain of CBP binds numerous transcription factors and several viral oncoproteins. We identified the Src substrate and RNA-binding protein Sam68 as novel CH3-binding protein. Sam68 binds the CH3 domain in part through a conserved FXD/EXXXL motif that is shared among several CH3-binding proteins, including the adenoviral oncoprotein E1A and the tumor suppressor p53. Sam68 and CBP interact in vivo and colocalize in nuclear sub-domains. Sam68 has potent transcriptional repression activity that is independent of its RNA binding activity, which suggests that RNA processing and regulation of gene expression by Sam68 are separable functions. Consistent with this, CBP did not stimulate the ability of Sam68 to promote Rev response element-containing mRNA export. Interestingly, Sam68 can regulate RNA processing in the absence of a Rev response element, suggesting that Sam68 functions through a novel RNA element. Together, these findings reveal a previously unidentified function for Sam68 as a transcriptional repressor and suggest that Sam68 might link cellular signaling pathways with components of the transcriptional machinery.
 ...
PMID:Physical and functional interaction between the transcriptional cofactor CBP and the KH domain protein Sam68. 1249 68

The formation of new blood vessels, angiogenesis, is an essential process during development and disease. Angiogenesis is well known as a crucial step in tumor growth and progression. Angiogenesis is induced by hypoxic conditions and regulated by the hypoxia-inducible factor 1 (HIF-1). The expression of HIF-1 correlates with hypoxia-induced angiogenesis as a result of the induction of the major HIF-1 target gene, vascular endothelial cell growth factor (VEGF). In this review, a brief overview of the mechanism of angiogenesis is discussed, focusing on the regulatory processes of the HIF-1 transcription factor. HIF-1 consists of a constitutively expressed HIF-1 beta (HIF-1beta) subunit and an oxygen-regulated HIF-1 alpha (HIF-1a) subunit. The stability and activity of HIF-1alpha are regulated by the interaction with various proteins, such as pVHL, p53, and p300/CBP as well as by post-translational modifications, hydroxylation, acetylation, and phosphorylation. It was recently reported that HIF-1alpha binds a co-activator of the AP-1 transcription factor, Jab-1, which inhibits the p53-dependent degradation of HIF-1 and enhances the transcriptional activity of HIF-1 and the subsequent VEGF expression under hypoxic conditions. ARD1 acetylates HIF-1alpha and stimulates pVHL-mediated ubiquitination of HIF-1alpha. With a growing knowledge of the molecular mechanisms in this field, novel strategies to prevent tumor angiogenesis can be developed, and from these, new anticancer therapies may arise.
 ...
PMID:Hypoxia-induced angiogenesis during carcinogenesis. 1254 82

Prostate cancer prevention by key elements present in human nutrients derived from plants and fruits has been confirmed in various cell cultures and tumor models. Resveratrol (RE), a phytoalexin, induces remarkable inhibitory effects in prostate carcinogenesis via diverse cellular mechanisms associated with tumor initiation, promotion and progression. Earlier studies have shown that RE alters the expression of genes involved in cell cycle regulation and apoptosis, including cyclins, cdks, p53 and cdk inhibitors. However, most of the p53-controlled effects related to the role of RE in transcription either by activation or repression of a sizable number of primary and secondary target genes have not been investigated. Our study examined whether RE activates a cascade of p53-directed genes that are involved in apoptosis mechanism(s) or whether it modifies the androgen receptor and its co-activators directly or indirectly and induces cell growth inhibition. We demonstrate by DNA microarray, RT-PCR, Western blot and immunofluorescence analyses that treatment of androgen-sensitive prostate cancer cells (LNCaP) with 10(-5) M RE for 48 hr downregulates prostate-specific antigen (PSA), AR co-activator ARA 24 and NF-kB p65. Altered expression of these genes is associated with an activation of p53-responsive genes such as p53, PIG 7, p21(Waf1-Cip1), p300/CBP and Apaf-1. The effect of RE on p300/CBP plays a central role in its cancer preventive mechanisms in LNCaP cells. Our results implicate activation of more than one set of functionally related molecular targets. At this point we have identified some of the key molecular targets associated with AR and p53 target genes. These findings point to the need for further extensive studies on AR co-activators, such as p300, its central role in post-translational modifications such as acetylation of p53 and/or AR by RE in a time- and dose-dependent manner at different stages of prostate cancer that will fully elucidate the role of RE as a chemopreventive agent for prostate cancer in humans.
 ...
PMID:Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. 2727 1

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.
 ...
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

p73 is a p53 homolog, as they are similar structurally and functionally. Unlike p53, p73 is not inactivated by the products of viral oncogenes such as SV40 T antigen and human papilloma virus E6. Here we show that the product of adenoviral oncogene E1A inhibits the transcriptional activation by both p73alpha and p73beta. Electrophoretic mobility shift assays revealed that E1A does not inhibit the sequence-specific DNA binding by p73. Transcriptional activation by a fusion protein containing the Gal4 DNA-binding domain and either of the activation domains of p73 was inhibited by wild-type (WT) E1A, but not by the N-terminal deletion mutant E1A(Delta2-36). E1A(Delta2-36), which does not bind to the p300/CBP family of coactivators, failed to inhibit p73-mediated transcription, whereas E1A(DeltaCR2), a deletion mutant that does not bind to the pRb family of proteins, inhibited p73-mediated transcription as efficiently as WT E1A. Consistent with these observations, growth arrest induced by p73 expressed from a recombinant adenovirus was abrogated by WT E1A, which correlated with inhibition of p73-mediated induction of p21(WAF1/CIP1) by E1A. However, p73 was able to induce p21(WAF1/CIP1) and to mediate growth arrest in the presence of E1A(Delta2-36). Furthermore, the expression of either wild-type E1A or E1A(Delta2-36) resulted in the stabilization of endogenous p73. However, p73 stabilized in response to the expression of E1A(Delta2-36), but not WT E1A, was able to activate the expression of p21(WAF1/CIP1). These results suggest that the transcriptional activation function of p73 is specifically targeted by E1A through a mechanism involving p300/CBP proteins during the process of transformation and that p73 may have a role to play as a tumor suppressor.
 ...
PMID:Regulation of the p53 homolog p73 by adenoviral oncogene E1A. 1263 67

Several viruses target cellular promyelocytic leukemia (PML)-nuclear bodies (PML-NBs) to induce their disruption, marked morphological changes in these structures or the relocation to PML-NB components to the cytoplasm of infected cells. PML conversely interferes with viral replication. We demonstrate that PML acts as a coactivator for the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein without direct binding. Tax was identified within interchromatin granule clusters (IGCs)/RNA splicing bodies (SBs), not PML-NBs; Tax expression did not affect PML-NB formation. Moreover, PML and CBP/p300 cooperatively activated Tax-mediated HTLV-1-LTR-dependent gene expression. Interestingly, two PML mutants, PML-RAR and PMLDelta216-331, which fail to form PML-NBs, could also coactivate Tax-mediated trans-acting function but had no effect on retinoic acid receptor (RAR)- or p53-dependent gene expression. In contrast, SMRT (silencing mediator for retinoic acid and thyroid hormone receptors), a nuclear corepressor found within the matrix-associated deacetylase (MAD) nuclear body, relocalized into Tax-associated nuclear bodies upon coexpression with Tax. SMRT coactivated the trans-acting function of Tax through direct binding. Coexpression of SMRT and PML resulted in an additive activation of Tax trans-acting function. Thus, crosstalk between distinct nuclear bodies may control Tax function.
 ...
PMID:Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein. 1264 64

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.
 ...
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.
 ...
PMID:Physical and functional interactions between PML and MDM2. 1275 44

The Eleven Lysine-rich Leukemia (ELL) gene undergoes translocation and fuses in frame to the Multiple Lineage Leukemia (MLL) gene in a substantial proportion of patients suffering from acute forms of leukemia. Molecular mechanisms of cellular transformation by the MLL-ELL fusion are not well understood. Although both MLL-ELL and wild-type ELL can reduce functional activity of p53 tumor suppressor, our data reveal that MLL-ELL is a much more efficient inhibitor of p53 than is wild-type ELL. We also demonstrate for the first time that ELL extreme C terminus [ELL(eCT)] is required for the recruitment of p53 into MLL-ELL nuclear foci and is both necessary and sufficient for the MLL-ELL inhibition of p53-mediated induction of p21 and apoptosis. Finally, our results demonstrate that MLL-ELL requires the presence of intact ELL(eCT) in order to disrupt p53 interactions with p300/CBP coactivator and thus significantly reduce p53 acetylation in vivo. Since ELL(eCT) has recently been shown to be both necessary and sufficient for MLL-ELL-mediated transformation of normal blood progenitors, our data correlate ELL(eCT) contribution to MLL-ELL transformative effects with its ability to functionally inhibit p53.
 ...
PMID:Molecular basis of p53 functional inactivation by the leukemic protein MLL-ELL. 1277 66


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