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)

SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1alpha directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.
 ...
PMID:Negative regulation of the deacetylase SIRT1 by DBC1. 1823 2

Sirt7 is a member of the mammalian sirtuin family consisting of 7 genes, Sirt1 to Sirt7, which all share a homology to the founding family member, the yeast Sir2 gene. Most sirtuins are supposed to act as histone/protein deacetylases, which use oxidized NAD in a sirtuin-specific, 2-step deacetylation reaction. To begin to decipher the biological role of Sirt7, we inactivated the Sirt7 gene in mice. Sirt7-deficient animals undergo a reduction in mean and maximum lifespans and develop heart hypertrophy and inflammatory cardiomyopathy. Sirt7 mutant hearts are also characterized by an extensive fibrosis, which leads to a 3-fold increase in collagen III accumulation. We found that Sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo and an increased rate of apoptosis in the myocardium of mutant mice. Sirt7-deficient primary cardiomyocytes show a approximately 200% increase in basal apoptosis and a significantly diminished resistance to oxidative and genotoxic stress suggesting a critical role of Sirt7 in the regulation of stress responses and cell death in the heart. We propose that enhanced activation of p53 by lack of Sirt7-mediated deacetylation contributes to the heart phenotype of Sirt7 mutant mice.
 ...
PMID:Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. 1823 38

Sirt2 is a mammalian member of the Sirtuin family of NAD(+) (nicotinamide adenine dinucleotide)-dependent protein deacetylases. Although Sir-2.1 (a Caenorhabditis elegans Sirt2 ortholog) has been reported to interact with PAR-5/FTT-2 (a C. elegans 14-3-3 homolog), the molecular significance of the interaction between Sirt2 and 14-3-3 proteins in mammalian cell is not understood. Here, we report that Sirt2 interacts with 14-3-3 beta and gamma among various 14-3-3 isoforms, and that this interaction is strengthened by AKT. Furthermore, Sirt2 deacetylates and down-regulates the transcriptional activity of p53, and 14-3-3 beta/gamma augment deacetylation and down-regulation of the p53 transcriptional activity by Sirt2 in an AKT-dependent manner. Treatment of cells with nicotinamide, an inhibitor of Sirtuins, relieves the inhibition of p53 by Sirt2 and 14-3-3 beta/gamma. Therefore, our results suggest that the interaction between Sirt2 and 14-3-3 beta/gamma is a novel mechanism for the negative regulation of p53 beside the well-characterized Mdm2-mediated repression.
 ...
PMID:Sirt2 interacts with 14-3-3 beta/gamma and down-regulates the activity of p53. 1824 87

The tumour suppressor p33(ING1b) ((ING1b) for inhibitor of growth family, member 1b) is important in cellular stress responses, including cell-cycle arrest, apoptosis, chromatin remodelling and DNA repair; however, its degradation pathway is still unknown. Recently, we showed that genotoxic stress induces p33(ING1b) phosphorylation at Ser 126, and abolishment of Ser 126 phosphorylation markedly shortened its half-life. Therefore, we suggest that Ser 126 phosphorylation modulates the interaction of p33(ING1b) with its degradation machinery, stabilizing this protein. Combining the use of inhibitors of the main degradation pathways in the nucleus (proteasome and calpains), partial isolation of the proteasome complex, and in vitro interaction and degradation assays, we set out to determine the degradation mechanism of p33(ING1b). We found that p33(ING1b) is degraded in the 20S proteasome and that NAD(P)H quinone oxidoreductase 1 (NQO1), an oxidoreductase previously shown to modulate the degradation of p53 in the 20S proteasome, inhibits the degradation of p33(ING1b). Furthermore, ultraviolet irradiation induces p33(ING1b) phosphorylation at Ser 126, which, in turn, facilitates its interaction with NQO1.
 ...
PMID:NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of the tumour suppressor p33(ING1b). 1838 57

Mammalian Delta(1)-pyrroline-5-carboxylate synthase (P5CS) is a bifunctional ATP- and NAD(P)H-dependent mitochondrial enzyme that catalyzes the coupled phosphorylation and reduction-conversion of L: -glutamate to P5C, a pivotal step in the biosynthesis of L: -proline, L: -ornithine and L: -arginine. Previously, we reported cloning and characterization of two P5CS transcript variants generated by exon sliding that encode two protein isoforms differing only by a two amino acid-insert at the N-terminus of the gamma-glutamyl kinase active site. The short form (P5CS.short) is highly expressed in the gut and is inhibited by ornithine. In contrast, the long form (P5CS.long) is expressed ubiquitously and is insensitive to ornithine. Interestingly, we found that all the established human cell lines we have studied expressed P5CS.long but not P5CS.short. In addition, expression of P5CS.long can be modulated by hormones: downregulation by hydrocortisone and dexamethasone and upregulation by estradiol, for example. Using a quantitative proteomic approach, we showed that P5CS.long is upregulated by p53 in p53-induced apoptosis in DLD-1 colorectal cancer cells. Functional genomic analysis confirmed that there are two p53-binding consensus sequences in the promoter region and in the intron 1 of the human P5CS gene. Interestingly, overexpression of P5CS by adenoviruses harboring P5CS.long or P5CS.short in various cell types has no effect on cell growth or survival. It would be of importance to further investigate the role of P5CS as a p53 downstream effector and how P5CS.short expression is regulated by hormones and factors of alternative splicing in cells isolated from model animals.
 ...
PMID:Human Delta1-pyrroline-5-carboxylate synthase: function and regulation. 1840 42

Benzo[a]pyrene (BaP) is a potentially genotoxic and cytotoxic environmental pollutant. Previous studies showed that exposure of HepG(2) cells to BaP causes necrotic cell death [Lin, T., Yang, M.S., 2007b. Cell death induced by benzo[a]pyrene in the HepG(2) cells is dependent on PARP-1 activation and NAD depletion. Toxicology 245, 147-153]. In the present study, the signaling pathways associated with this response was studied. BaP induced accumulation and activation of p53 in HepG(2) cells, which occurred as early as 12h after exposure. Activation of p53 was evidenced by its phosphorylation at serine 15 (Ser15) and acetylation at lysine 382 (Lys382). Chemical inhibition and siRNA-mediated knockdown of p53 expression suppressed its phosphorylation as well as cell death. BaP also activated p38 MAPK and ERK, but not JNK, at 6h after exposure. SB203580 and PD98059, specific inhibitors of p38 MAPK and ERK, respectively, suppressed phosphorylation of p53 at Ser15, but the accumulation of p53 was only moderately reduced. Acetylation of p53 at Lys 382 was not affected by these inhibitors, suggesting that acetylation stabilizes p53 in response to DNA damage. SB203580 and PD98059 prevented downstream energy failure and BaP-induced cell death. Similar results were obtained with siRNA against two isoforms of p38 MAPK, p38alpha and p38beta. Wortmannin, selective inhibitor of DNA-PK and ATM/ATR, abolished p53 phosphorylation, indicating an involvement of multiple pathways of p53 phosphorylation upon exposure to BaP. In summary, the current study demonstrated that both MAPK and p53 activation are required for BaP-induced necrotic cell death. The results also provide a novel model for studying the regulation between p53 and p38 MAPK in the progression of cellular necrosis.
 ...
PMID:MAPK regulate p53-dependent cell death induced by benzo[a]pyrene: involvement of p53 phosphorylation and acetylation. 1840 7

Deleted in Breast Cancer-1 (DBC1) and its paralog CARP-1 are large multi-domain proteins, with a nuclear or perinuclear localization, and a role in promoting apoptosis upon processing by caspases. Recent studies on human DBC1 show that it is a specific inhibitor of the sirtuin-type deacetylase, Sirt1, which deacetylates histones and p53. Using sensitive sequence profile searches and HMM-HMM comparisons we show that the central conserved globular domain present in the DBC1 and it homologs from diverse eukaryotes is a catalytically inactive version of the Nudix hydrolase (MutT) domain. Given that Nudix domains are known to bind nucleoside diphosphate sugars and NAD, we predict that this domain in DBC1 and its homologs binds NAD metabolites such as ADP-ribose. Hence, we propose that DBC1 and its homologs are likely to regulate the activity of SIRT1 or related deacetylases by sensing the soluble products or substrates of the NAD-dependent deacetylation reaction. The complex domain architectures of the members of the DBC1 family, which include fusions to the RNA-binding S1-like domain, the DNA-binding SAP domain and EF-hand domains, suggest that they are likely to function as integrators of distinct regulatory signals including chromatin protein modification, soluble compounds in NAD metabolism, apoptotic stimuli and RNA recognition.
 ...
PMID:Analysis of DBC1 and its homologs suggests a potential mechanism for regulation of sirtuin domain deacetylases by NAD metabolites. 1841 69

Chronic alcohol consumption affects the gene expression of a NAD-dependent deacetylase Sirtuis 1 (SIRT1) and the peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC-1alpha). Our aim was to verify that it also alters the forkhead (FoxO1) and p53 transcription factor proteins, critical in the hepatic response to oxidative stress and regulated by SIRT1 through its deacetylating capacity. Accordingly, rats were pair-fed the Lieber-DeCarli alcohol-containing liquid diets for 28 days. Alcohol increased hepatic mRNA expression of FoxO1 (p=0.003) and p53 (p=0.001) while corresponding protein levels remained unchanged. However phospho-FoxO1 and phospho-Akt (protein kinase) were both decreased by alcohol consumption (p=0.04 and p=0.02, respectively) while hepatic p53 was found hyperacetylated (p=0.017). Furthermore, mitochondrial SIRT5 was reduced (p=0.0025), and PGC-1alpha hyperacetylated (p=0.027), establishing their role in protein modification. Thus, alcohol consumption disrupts nuclear-mitochondrial interactions by post-translation protein modifications, which contribute to alteration of mitochondrial biogenesis through the newly discovered reduction of SIRT5.
 ...
PMID:Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function. 1855 8

NAD(P)H:quinoneoxidoreductase 1 (NQO1) inhibits some cancers and increases p53 and apoptosis in cells. Due to an inactivating polymorphism, 10% of humans have no NQO1 activity. A case:control study suggested that chronic lymphocytic leukemia (CLL) patients may have an increased incidence of the NQO1 null genotype compared with controls. NQO1 genotype did not correlate with various CLL prognostic factors, but we observed a trend toward lower drug response in patients with the NQO1 null genotype. Inhibiting NQO1 activity decreased p53 levels and drug induced apoptosis in CLL cells. These results raise the possibility that the NQO1 polymorphism may be a risk factor for CLL and a predictor of response to chemotherapy.
 ...
PMID:Investigation of an NQO1 polymorphism as a possible risk and prognostic factor for chronic lymphocytic leukemia. 1867 18

Malignant astrocytomas comprise anaplastic astrocytoma (AA; grade III) and Glioblastoma (GBM; grade IV). GBM is the most malignant with a median survival of 10-12 months in patients. Using cDNA microarray based expression profiling of different grades of astrocytomas, we identified several fold increased levels of PBEF1 transcripts in GBM samples. Pre-B-cell colony enhancing factor 1 gene (PBEF1) encodes Nicotinamide phosphoribosyltransferase (NAmPRTase), which catalyses the rate limiting step in the salvage pathway of NAD metabolism in mammalian cells. Further validation using real time RT-qPCR on an independent set of tumor samples (n=91) and normal brain samples (n=9), GBM specific higher expression of PBEF1 was confirmed. Immunohistochemical staining for PBEF1 on a subset of the above samples largely reinforced our finding. We carried out ELISA analysis on serum samples of astrocytoma patients to determine whether this protein levels would correlate with the presence of tumor and tumor grade. PBEF1 serum levels were substantially elevated in many of the AA and GBM patients. Statistical analysis of these data indicates that in patients with astrocytoma, serum PBEF1 levels correlate with tumor grade and is highest in GBM. Immunohistochemical analysis of an independent set of 51 retrospective GBM cases with known survival data revealed that PBEF1 expression in the tumor tissue along with its co-expression with p53 was associated with poor survival. Thus, we have identified PBEF1 as a potential malignant astrocytoma serum marker and prognostic indicator among GBMs.
 ...
PMID:PBEF1/NAmPRTase/Visfatin: a potential malignant astrocytoma/glioblastoma serum marker with prognostic value. 1872 3


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