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)

TP53 (tumor protein p53; p53) regulates its target genes under various cellular stresses. By combining chromatin immunoprecipitation with oligonucleotide microarrays, we have mapped binding sites of p53 (p53-BS) in the genome of HCT116 human colon carcinoma cells, along with those of acetylated H3, acetylated H4, and methylated H3-K4. We analyzed a 30-Mb portion of the human genome selected as a representative model by the ENCODE Consortium. In the region, we found 37 p53-BS, of which the p53-binding motif was present in 32 (86%). Acetylated histone H3 and H4 were detected at 14 (38%) and 33 (89%) of the p53-BS, respectively. A significant portion (58%) of H4 acetylation in the p53-BS was not accompanied by H3 acetylation. Acetyl H3 were preferentially located at the 5' and 3' ends of genes, whereas acetyl H4 were distributed widely across the genome. These results provide novel insights into how p53 binding coordinates with histone modification in human.
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PMID:An integrated map of p53-binding sites and histone modification in the human ENCODE regions. 1708 12

Sir2 (silent information regulator 2) is an NAD(+)-dependent histone deacetylase that contributes to longevity in yeast. SIRT1, a mammalian Sir2 ortholog, deacetylates histones and various transcription factors, including p53, FOXO proteins, and peroxisome proliferator-activated receptor-gamma. We found that its subcellular localization varied in different tissues of the adult mouse. Some subsets of neurons predominantly expressed SIRT1 in the cytoplasm, but ependymal cells expressed it in both the nucleus and cytoplasm. On the other hand, spermatocytes expressed SIRT1 only in the nucleus. Cardiomyocytes in the day 12.5 mouse embryo expressed SIRT1 exclusively in the nucleus, but in the adult heart, they expressed it in both the cytoplasm and nucleus. C2C12 myoblast cells expressed SIRT1 in the nucleus, but it localized to the cytoplasm after differentiation. LY294002, an inhibitor of phosphoinositide 3-hydroxykinase, strongly inhibited the nuclear localization of SIRT1 in undifferentiated C2C12 cells. In a heterokaryon assay, SIRT1 shuttled between the nucleus and cytoplasm, and leptomycin B, an inhibitor of CRM1-mediated nuclear exportation, inhibited this shuttling. Two nuclear localization signals and two nuclear export signals were identified by deletion and site-directed mutation analyses. Overexpressed nuclear (but not cytoplasmic or dominant-negative) SIRT1 enhanced the deacetylation of histone H3 in C2C12 cells. Moreover, only the nuclear form suppressed the apoptosis of C2C12 cells induced by antimycin A, an oxidative stressor. These findings indicate that nucleocytoplasmic shuttling is a novel regulatory mechanism of SIRT1, which may participate in differentiation and in inhibition of cell death.
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PMID:Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. 1719 3

Ligand activation of Notch leads to the release of Notch IC (the intracellular receptor domain), which translocates to the nucleus and interacts with the DNA-binding protein CSL to control expression of specific target genes. In addition to ligand-mediated activation, Notch signalling can be further modulated by interactions of Notch IC with a number of other proteins. MAML1 has previously been shown to act co-operatively with the histone acetyltransferase p300 in Notch IC-mediated transcription. In the present study we show that the N-terminal domain of MAML1 directly interacts with both p300 and histones, and the p300-MAML1 complex specifically acetylates histone H3 and H4 tails in chromatin. Furthermore, p300 acetylates MAML1 and evolutionarily conserved lysine residues in the MAML1 N-terminus are direct substrates for p300-mediated acetylation. The N-terminal domain of MAML1 contains a proline repeat motif (PXPAAPAP) that was previously shown to be present in p53 and important for the p300-p53 interaction. We show that the MAML1 proline repeat motif interacts with p300 and enhances the activity of the MAML1 N-terminus in vivo. These findings suggest that the N-terminal domain of MAML1 plays an important role in Notch-regulated transcription, by direct interactions with Notch, p300 and histones.
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PMID:A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1. 1730 Feb 19

Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-XL and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidyl-inositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumin-induced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspase-dependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.
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PMID:Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer. 1733 30

FK228 (depsipeptide) is a novel histone deacetylase inhibitor (HDACI) that has shown therapeutical efficacy in clinical trials for malignant lymphoma. In this article, we examined in vitro effects of FK228 on human leukemia cell lines, NB4 and HL-60. FK228 alone (0.2-1 ng/mL) inhibited leukemia cell growth in a dose-dependent manner and induced death by apoptosis. FK228 had selective differentiating effects on two cell lines when used for 6 h before induction of granulocytic differentiation by retinoic acid (RA) or in combination with RA. These effects were accompanied by a time- and dose-dependent histone H4 hyper-acetylation or histone H3 dephosphorylation and alterations in DNA binding of NF-kappaB in association with cell death and differentiation. Pifithrin-alpha (PFT), an inhibitor of p53 transcriptional activity, protected only NB4 cells with functional p53 from FK228-induced apoptosis and did not interfere with antiproliferative activity in p53-negative HL-60 cells. In NB4 cells, PFT inhibited p53 binding to the p21 (Waf1/Cip1) promotor and induced DNA binding of NF-kappaB leading to enhanced cell survival. Thus, beneficial effects of FK228 on human promyelocytic leukemia may be exerted through the induction of differentiation or apoptosis via histone modification and selective involvement of transcription factors, such as NF-kappaB and p53.
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PMID:The histone deacetylase inhibitor FK228 distinctly sensitizes the human leukemia cells to retinoic acid-induced differentiation. 1734 29

The pathophysiology of cerebral ischemia involves multiple mechanisms including neuroinflammation mediated by activated microglia and infiltrating macrophages/monocytes. The present study employed a rat permanent middle cerebral artery occlusion (pMCAO) model to study effects of histone deacetylase (HDAC) inhibition on ischemia-induced brain infarction, neuroinflammation, gene expression, and neurological deficits. We found that post-pMCAO injections with HDAC inhibitors, valproic acid (VPA), sodium butyrate (SB), or trichostatin A (TSA), decreased brain infarct volume. Postinsult treatment with VPA or SB also suppressed microglial activation, reduced the number of microglia, and inhibited other inflammatory markers in the ischemic brain. The reduction in levels of acetylated histone H3 in the ischemic brain was prevented by treatment with VPA, SB, or TSA. Moreover, injections with HDAC inhibitors superinduced heat-shock protein 70 and blocked pMCAO-induced down-regulation of phospho-Akt, as well as ischemia-elicited up-regulation of p53, inducible nitric oxide synthase, and cyclooxygenase-2. The motor, sensory, and reflex performance of pMCAO rats was improved by VPA, SB, or TSA treatment. The beneficial effects of SB and VPA in reducing brain infarct volume and neurological deficits occurred when either drug was administrated at least 3 h after ischemic onset, and the behavioral improvement was long-lasting. Together, our results demonstrate robust neuroprotective effects of HDAC inhibitors against cerebral ischemia-induced brain injury. The neuroprotection probably involves multiple mechanisms including suppression of ischemia-induced cerebral inflammation. Given that there is no effective treatment for stroke, HDAC inhibitors, such as VPA, SB, and TSA, should be evaluated for their potential use for clinical trials in stroke patients.
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PMID:Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. 1737 5

Tumor suppressor genes are often silenced in human cancer; this can occur by transcriptional repression by deacetylation in the promoter regions, mediated by histone deacetylase (HDAC). HDAC inhibitors can block cancer cell growth by restoring expression of tumor suppressor genes. In this study, we investigated the effects of a HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) on pancreatic cancer cells. SAHA inhibited the growth of 6 pancreatic cancer cell lines in a dose-dependent manner as measured by MTT and clonogenic assays (ED(50) approximately 10(-6) M) associated with induction of apoptosis, G2 cell cycle arrest and also induced differentiation as indicated by morphology and increased expression of cytokeratin 7. It increased expression of p21(WAF1) (independent of the mutational status of p53), C/EBPalpha, RARalpha and E-cadherin; these genes have been associated with decreased proliferation in other cancers. SAHA decreased cyclin B1 expression; this cyclin normally promotes progression through G2 of the cell cycle. SAHA mediated acetylation of histone H3 globally, as well as, associated with the p21(WAF1) promoter, as measured by chromatin immunoprecipitation. SAHA also decreased levels of c-myc and cyclin D1, independent of an active beta-catenin pathway. In further studies, the combination of SAHA and an inhibitor of DNA methylation, 5-Aza-2'-deoxycytidine, had an enhanced antiproliferative effect on pancreatic cancer cells. In summary, SAHA inhibited the growth of human pancreatic cancer cells by inducing apoptosis, differentiation and cell cycle arrest, as well as increase in the expression of several tumor suppressor genes. SAHA is a novel, promising therapeutic agent for human pancreatic cancers.
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PMID:Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. 1741 71

Previous studies have indicated that d,l-sulforaphane (SFN), a synthetic cancer chemopreventive analogue of cruciferous vegetable-derived isomer (-)-1-isothiocyanato-(4R)-(methylsulfinyl)-butane, activates a checkpoint kinase 2 (Chk2)-dependent G(2)-M phase cell cycle arrest in p53-deficient human prostate cancer cells. Because p53 is a downstream target of Chk2 kinase and known to regulate G(2)-M transition by transcriptional regulation of cyclin-dependent kinase (Cdk) inhibitor p21(Cip1/Waf1) (p21), the present study was undertaken to determine the role of p21 in SFN-induced cell cycle arrest using wild-type p53-expressing cell line LNCaP. The SFN treatment caused a modest increase in S phase fraction and a marked increase in G(2)-M fraction in LNCaP cells in a concentration- and time-dependent manner. The SFN-induced S phase arrest correlated with a reduction in protein levels of cyclin D1, cyclin E, Cdk4, and Cdk6, whereas activation of the G(2)-M checkpoint was accompanied by induction of cyclin B1 and down-regulation of Cdk1 and Cdc25C protein levels. The SFN-treated LNCaP cells were also arrested in mitosis as revealed by immunofluorescence microscopy and increased Ser(10) phosphorylation of histone H3, a sensitive marker for mitotic cells. The SFN treatment increased activating phosphorylation of Chk2 (Thr(68)) that was accompanied by induction of p53 and p21. The SFN-induced mitotic arrest was statistically significantly increased by small interfering RNA-based knockdown of p21. However, p21 protein knockdown did not have any appreciable effect on SFN-induced cytoplasmic histone-associated DNA fragmentation (apoptosis). In conclusion, the present study indicates that induction of p21 protects against SFN-induced mitotic arrest in LNCaP cells.
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PMID:Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line. 1751 15

Oncogene-induced senescence is an important mechanism by which normal cells are restrained from malignant transformation. Here we report that the suppression of the c-Myc (MYC) oncogene induces cellular senescence in diverse tumor types including lymphoma, osteosarcoma, and hepatocellular carcinoma. MYC inactivation was associated with prototypical markers of senescence, including acidic beta-gal staining, induction of p16INK4a, and p15INK4b expression. Moreover, MYC inactivation induced global changes in chromatin structure associated with the marked reduction of histone H4 acetylation and increased histone H3 K9 methylation. Osteosarcomas engineered to be deficient in p16INK4a or Rb exhibited impaired senescence and failed to exhibit sustained tumor regression upon MYC inactivation. Similarly, only after lymphomas were repaired for p53 expression did MYC inactivation induce robust senescence and sustained tumor regression. The pharmacologic inhibition of signaling pathways implicated in oncogene-induced senescence including ATM/ATR and MAPK did not prevent senescence associated with MYC inactivation. Our results suggest that cellular senescence programs remain latently functional, even in established tumors, and can become reactivated, serving as a critical mechanism of oncogene addiction associated with MYC inactivation.
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PMID:Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. 1766 22

The p53 tumor suppressor protein regulates many genes that can determine different cellular outcomes such as growth arrest or cell death. Promoter-selective transactivation by p53, although critical for the different cellular outcomes, is not well understood. We report here that the human cellular apoptosis susceptibility protein (hCAS/CSE1L) associates with a subset of p53 target promoters, including PIG3, in a p53-autonomous manner. Downregulation of hCAS/CSE1L decreases transcription from those p53 target promoters to which it preferentially binds and reduces apoptosis. In addition, hCAS/CSE1L silencing leads to increased methylation of histone H3 lysine 27 within the PIG3 gene. hCAS/CSE1L was previously shown to function as a nucleo-cytoplasmic transport factor, as does its closely related yeast homologue Cse1, which can also associate with chromatin and serve as a barrier protein that prevents spreading of heterochromatin. Thus, human CAS/CSE1L can bind select genes with significant functional consequences for p53-mediated transcription and determine cellular outcome.
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PMID:hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes. 1771 38


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