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)

Histone deacetylases (HDACs) regulate transcription and specific functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACI) possess anti-tumor activity and are well tolerated, suggesting that they might develop into a specific strategy for cancer treatment. Indeed, HDACIs have successfully entered clinical trials, but the molecular basis for their selective anti-tumor activities is not clear. Recent work on leukemias expressing the PML-RAR or AML1-ETO oncogenes, known to initiate leukemogenesis through deregulation of HDACs, shows that HDACIs induce massive blast-cell apoptosis. Interestingly, the pro-apoptotic activity of the drug is not due to the relief of oncogene-mediated inhibition of the p53 tumor-suppressor pathway but, instead, relies on the selective upregulation of the death receptors DR5 and Fas and their cognate ligands TRAIL and FasL. Significantly, normal myeloid progenitors are not sensitive to HDACI-induced apoptosis and oncogene expression is not sufficient to confer HDACI-sensitivity to normal cells, demonstrating that sensitivity to HDACI is a property of the fully transformed phenotype. In principle, our findings could thus apply to other cancers, where the contribution of HDACs to tumorigenesis is not yet defined.
 ...
PMID:Mechanisms of selective anticancer action of histone deacetylase inhibitors. 1590 87

Histone deacetylases (HDACs) are generally thought to play important roles in human disease. However, little information is available concerning the specific functions of individual HDACs. We previously reported on transgenic mice that expressed human HDAC1 and experienced steatosis and nuclear pleomorphism in their hepatic tissues. To find out if the over-expression of HDAC1 contributes to the expression of genes related to the cell cycle, apoptosis, and lipid metabolism that eventually contribute to the pathological changes in the livers of the transgenic mice, the expression profiles of the related genes in liver tissues were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The activated human HDAC1 significantly induced the expression levels of mRNA for p53, PPAR-gamma and Bak and reduced the p21 expression level compared with the levels in control littermates. However, the protein levels of p53 and PPAR-gamma were significantly decreased. In conclusion, our results indicate that HDAC1 can regulate gene expression at the mRNA and protein levels independently and that this may be a potential cytopathic factor for hepatic tissue in transgenic mice that over-express HDAC1.
 ...
PMID:Histone deacetylase 1 contributes to cell cycle and apoptosis. 1620 56

Histone H2AX promotes DNA double-strand break (DSB) repair and immunoglobulin heavy chain (IgH) class switch recombination (CSR) in B-lymphocytes. CSR requires activation-induced cytidine deaminase (AID) and involves joining of DSB intermediates by end joining. We find that AID-dependent IgH locus chromosome breaks occur at high frequency in primary H2AX-deficient B cells activated for CSR and that a substantial proportion of these breaks participate in chromosomal translocations. Moreover, activated B cells deficient for ATM, 53BP1, or MDC1, which interact with H2AX during the DSB response, show similarly increased IgH locus breaks and translocations. Thus, our findings implicate a general role for these factors in promoting end joining and thereby preventing DSBs from progressing into chromosomal breaks and translocations. As cellular p53 status does not markedly influence the frequency of such events, our results also have implications for how p53 and the DSB response machinery cooperate to suppress generation of lymphomas with oncogenic translocations.
 ...
PMID:H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. 1642 10

Activation of the tumor suppressor protein p53 is a critical cellular response to various stress stimuli and to inappropriate activity of growth-promoting proteins, such as Myc, Ras, E2F, and beta-catenin. Protein stability and transcriptional activity of p53 are modulated by protein-protein interactions and post-translational modifications, including acetylation. Here, we show that inappropriate activity of prothymosin alpha (PTMA), an oncoprotein overexpressed in human cancers, triggers a p53 response. Overexpression of PTMA enhanced p53 transcriptional activity in reporter gene assays for p53 target gene promoters hdm2, p21, and cyclin G. Overexpressed PTMA resulted in increased mRNA and protein levels for endogenous p53 target genes, hdm2 and p21, and in growth suppression. In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity. Histone acetyltransferases (HATs) act as p53 coactivators and acetylate p53. PTMA, known to interact with HATs, led to increased levels of acetylated p53. PTMA did not increase the transcriptional activity of an acetylation-deficient p53 mutant, suggesting that p53 acetylation is an indispensable part of the p53 response to PTMA. Chromatin immunoprecipitation assays showed that excess PTMA associates with the p21 promoter and results in increased levels of acetylated p53 at the p21 promoter. Our findings indicate that overexpressed PTMA elicits a p53 response that involves p53 acetylation.
 ...
PMID:Overexpression of the oncoprotein prothymosin alpha triggers a p53 response that involves p53 acetylation. 1654 Jun 64

Histone methylation regulates chromatin structure, transcription, and epigenetic state of the cell. Histone methylation is dynamically regulated by histone methylases and demethylases such as LSD1 and JHDM1, which mediate demethylation of di- and monomethylated histones. It has been unclear whether demethylases exist that reverse lysine trimethylation. We show the JmjC domain-containing protein JMJD2A reversed trimethylated H3-K9/K36 to di- but not mono- or unmethylated products. Overexpression of JMJD2A but not a catalytically inactive mutant reduced H3-K9/K36 trimethylation levels in cultured cells. In contrast, RNAi depletion of the C. elegans JMJD2A homolog resulted in an increase in general H3-K9Me3 and localized H3-K36Me3 levels on meiotic chromosomes and triggered p53-dependent germline apoptosis. Additionally, other human JMJD2 subfamily members also functioned as trimethylation-specific demethylases, converting H3-K9Me3 to H3-K9Me2 and H3-K9Me1, respectively. Our finding that this family of demethylases generates different methylated states at the same lysine residue provides a mechanism for fine-tuning histone methylation.
 ...
PMID:Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. 1660 38

Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that alpha, beta unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degradation of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addition to inducing p300 degradation curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent association with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compound for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
 ...
PMID:Curcumin is an inhibitor of p300 histone acetylatransferase. 1678 65

Epigenetic processes such as DNA methylation and histone modifications are now recognized as critical events for regulation of gene expression in mammalian cells and affect gene function without a change in coding sequence. Neoplastic cells often show profound epigenetic alterations that contribute to tumorigenesis by altering expression of critical genes. In colorectal tumorigenesis, detailed analysis led to a hypothesis on a critical role for epigenetic changes in age-related cancer susceptibility and separately identified a distinct phenotype termed the CpG island methylator phenotype. CpG island methylator phenotype-positive colorectal cancers have significant associations with female sex, older age, proximal location, mucinous histology, KRAS and BRAF mutations, wild-type p53, and microsatellite instability. Histone modifications that affect chromatin structures are also closely implicated in tumor suppressor gene inactivation and DNA methylation and histone modifications seem to form reinforcing networks for stable gene silencing. Much of the excitement in this field relates to the possibility of therapeutic reversal of epigenetic changes by chromatin-modifying drugs. In CpG island methylator phenotype-positive colorectal cancers, DNA methylation inhibitors restore key silenced pathways in vivo (eg, mismatch repair defects), and hypomethylation can largely abolish tumorigenesis in a mouse model. Drugs that inhibit DNA methylation and histone deacetylation are in use in the clinic and should be tested in colorectal malignancy.
 ...
PMID:Targeting aberrant chromatin structure in colorectal carcinomas. 1746 46

Histone modifications such as acetylation, methylation and phosphorylation have been implicated in fundamental cellular processes such as epigenetic regulation of gene expression, organization of chromatin structure, chromosome segregation, DNA replication and DNA repair. Males absent on the first (MOF) is responsible for acetylating histone H4 at lysine 16 (H4K16) and is a key component of the MSL complex required for dosage compensation in Drosophila. The human ortholog of MOF (hMOF) has the same substrate specificity and recent purification of the human and Drosophila MOF complexes showed that these complexes were also highly conserved through evolution. Several studies have shown that loss of hMOF in mammalian cells leads to a number of different phenotypes; a G2/M cell cycle arrest, nuclear morphological defects, spontaneous chromosomal aberrations, reduced transcription of certain genes and an impaired DNA repair response upon ionizing irradiation. Moreover, hMOF is involved in ATM activation in response to DNA damage and acetylation of p53 by hMOF influences the cell's decision to undergo apoptosis instead of a cell cycle arrest. These data, highlighting hMOF as an important component of many cellular processes, as well as links between hMOF and cancer will be discussed.
 ...
PMID:Males absent on the first (MOF): from flies to humans. 1769 80

p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. Histone lysine methylation has recently been shown to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.
 ...
PMID:p53 is regulated by the lysine demethylase LSD1. 1780 99

Histone H2AX is required to maintain genomic stability in cells and to suppress malignant transformation of lymphocytes in mice. H2ax(-/-)p53(-/-) mice succumb predominantly to immature alphabeta T-cell lymphomas with translocations, deletions, and genomic amplifications that do not involve T-cell receptor (TCR). In addition, H2ax(-/-)p53(-/-) mice also develop at lower frequencies B and T lymphomas with antigen receptor locus translocations. V(D)J recombination is initiated through the programmed induction of DNA double-strand breaks (DSBs) by the RAG1/RAG2 endonuclease. Because promiscuous RAG1/RAG2 cutting outside of antigen receptor loci can promote genomic instability, H2ax(-/-)p53(-/-) T-lineage lymphomas might arise, at least in part, through erroneous V(D)J recombination. Here, we show that H2ax(-/-)p53(-/-)Rag2(-/-) mice exhibit a similar genetic predisposition as do H2ax(-/-)p53(-/-) mice to thymic lymphoma with translocations, deletions, and amplifications. We also found that H2ax(-/-)p53(-/-)Rag2(-/-) mice often develop thymic lymphomas with loss or deletion of the p53(+) locus. Our data show that aberrant V(D)J recombination is not required for rapid onset of H2ax/p53-deficient thymic lymphomas with genomic instability and that H2ax deficiency predisposes p53(-/-)Rag2(-/-) thymocytes to transformation associated with p53 inactivation. Thus, H2AX is essential for suppressing the transformation of developing thymocytes arising from the aberrant repair of spontaneous DSBs.
 ...
PMID:Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations. 1904 71


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