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)

Sirtuins are a family of nicotinamide adenine dinucleotide (NAD(+))-dependent enzymes catalyzing the deacetylation of acetyl-lysine residues of histones and other proteins. Three 9-fluorenylmethoxycarbonyl (Fmoc)-labeled peptide substrates derived from the amino acid sequence of p53, i.e. Fmoc-KK(Ac)-NH(2), Fmoc-KK(Ac)L-NH(2) and Fmoc-RHKK(Ac)-NH(2), were synthesized and evaluated as substrates of the human isoenzyme SIRT1. The acetylated and respective deacetylated peptides as well as nicotinamide as the reaction product of nicotinamide adenine dinucleotide were separated by capillary electrophoresis in a fused-silica capillary using 200 mM phosphate-Tris buffer, pH 2.7. Sodium hydroxide-mediated sample stacking was performed in order to overcome peak asymmetry due to the high salt and acid content of the sample as well as to enhance UV detection sensitivity. The assay was subsequently validated. Upon incubation of the acetylated peptides for 60 min in the presence of 2.5 U of SIRT1 at least 87% of the peptides was deacetylated, indicating that the new derivatives are efficient substrates of the enzyme.
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PMID:Development of a capillary electrophoresis-based assay of sirtuin enzymes. 1885 Jun 41

SIRT1 belongs to the sirtuin family of NAD(+)-dependent histone/protein deacetylases. Experimentally, increased activity of SIRT1 facilitates calorie-restricted longevity, and decreases NF-kappaB activation and the amount of the amyloid-beta (Abeta). We studied SIRT1 in an aging-associated muscle disease, sporadic inclusion-body myositis (s-IBM), whose muscle fibers contain increased NF-kappaB activation and abnormal accumulation of Abeta. We show that, as compared to the age-matched controls, in s-IBM muscle fibers: (1) SIRT1 activity and deacetylation of SIRT1 targets, H4, NF-kappaB and p53 were decreased; (2) SIRT1 mRNA and protein were significantly increased; (3) in the cytoplasm, SIRT1 protein was accumulated in the form of cytoplasmic aggregates; (4) in the nuclei, SIRT1 protein was decreased. To our knowledge, this is the first demonstration of SIRT1 abnormalities, including decreased SIRT1 deacetylase activity, in human disease associated with aging. We propose that in s-IBM muscle fibers, inadequate activity of SIRT1 may be detrimental by increasing NF-kappaB activation and contributing to abnormal Abeta accumulation. Improving SIRT1 action by treatment with known SIRT1 activators might benefit s-IBM patients.
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PMID:Decreased SIRT1 deacetylase activity in sporadic inclusion-body myositis muscle fibers. 1892 3

The NAD(+)-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1alpha, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation.
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PMID:Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. 1904 67

SIRT1 is a multifaceted, NAD(+)-dependent protein deacetylase that is involved in a wide variety of cellular processes from cancer to ageing. The function of SIRT1 in cancer is complex: SIRT1 has been shown to have oncogenic properties by downregulating p53 activity, but recent studies indicate that SIRT1 acts as a tumour suppressor in a mutated p53 background, raising intriguing questions regarding its mechanism of action. Here we discuss the current understanding of how SIRT1 functions in light of recent discoveries and propose that the net outcome of the seemingly opposite oncogenic and tumour-suppressive effects of SIRT1 depends on the status of p53.
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PMID:How does SIRT1 affect metabolism, senescence and cancer? 1913 7

Cardiovascular disease (CVD) is the most prevalent disease worldwide and there is intense interest in pharmaceutical approaches to reduce the burden of this chronic, aging-related condition. The sirtuin (SIRT) family of NAD(+)-dependent protein deacetylases and ADP-ribosyltransferases have emerged as exciting targets for CVD management that can impact the cardiovascular system both directly and indirectly, the latter by modulating whole body metabolism. SIRT1-4 regulate the activities of a variety of transcription factors, coregulators, and enzymes that improve metabolic control in adipose tissue, liver, skeletal muscle, and pancreas, particularly during obesity and aging. SIRT1 and 7 can control myocardial development and resist stress- and aging-associated myocardial dysfunction through the deacetylation of p53 and forkhead box O1 (FoxO1). By modulating the activity of endothelial nitric oxide synthase (eNOS), FoxO1, and p53, and the expression of angiotensin II type 1 receptor (AT1R), SIRT1 also promotes vasodilatory and regenerative functions in endothelial and smooth muscle cells of the vascular wall. Given the array of potentially beneficial effects of SIRT activation on cardiovascular health, interest in developing specific SIRT agonists is well-substantiated. Because SIRT activity depends on cellular NAD+ availability, enzymes involved in NAD+ biosynthesis, including nicotinamide phosphoribosyltransferase (Nampt), may also be valuable pharmaceutical targets for managing CVD. Herein we review the actions of the SIRT proteins on the cardiovascular system and consider the potential of modulating SIRT activity and NAD+ availability to control CVD.
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PMID:NAD(+), sirtuins, and cardiovascular disease. 1914 6

The NAD(+)-dependent histone deacetylase hSirT1 regulates cell survival and stress responses by inhibiting p53-, NF-kappaB-, and E2F1-dependent transcription. Here we show that the hSirT1/PCAF interaction controls the E2F1/p73 apoptotic pathway. hSirT1 represses E2F1-dependent P1p73 promoter activity in untreated cells and inhibits its activation in response to DNA damage. hSirT1, PCAF, and E2F1 are corecruited in vivo on theP1p73 promoter. hSirT1 deacetylates PCAF in vitro and modulates PCAF acetylation in vivo. In cells exposed to apoptotic DNA damage, nuclear NAD(+) levels decrease and inactivate hSirT1 without altering the hSirT1 interaction with PCAF and hSirT1 binding to the P1p73 promoter. The reactivation of hSirT1 by pyruvate that increases the [NAD(+)]/[NADH] ratio completely abolished the DNA damage-induced activation of TAp73 expression, thus linking the modulation of chromatin-bound hSirT1 deacetylase activity by the intracellular redox state with P1p73 promoter activity. The release of PCAF from hSirT1 repression favors the assembly of transcriptionally active PCAF/E2F1 complexes onto the P1p73 promoter and p53-independent apoptosis. Our results identify hSirT1 and PCAF as potential targets to modulate tumor cell survival and chemoresistance irrespective of p53 status.
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PMID:hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage. 1918 49

SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent histone/protein deacetylase, has been extensively studied recently for its critical role in the regulation of physiology, calorie restriction and aging. Studies on laboratory mice showed that expression of SIRT1 can be induced by starvation in a p53-dependent manner and requires the p53-binding sites present in the Sirt1 promoter. However, it remains to be determined whether these findings based on rodents apply to human beings. In this paper, we characterized a putative p53-binding element in the human SIRT1 promoter that might be required for the up-regulation of SIRT1 in response to nutritional stress. The p53-binding site in the promoter of human SIRT1 is more deviant from the consensus sequence than the corresponding sequence in the mouse Sirt1. There is a C to A change at the second half site in human SIRT1, thus disrupting the core-binding element CWWG in the canonical RRRCWWGYYY. To test whether such sequence change would affect its binding with p53 and the SIRT1 expression under stress, we studied various human cell lines with different p53 status and cells with ectopic expression of functionally distinct p53. We found that serum withdrawal also up-regulates human SIRT1 gene expression in a p53-dependent manner and that the p53-binding element in SIRT1 is required for the up-regulation. Thus, the mechanism responsible for the regulation of SIRT1 expression by p53 is conserved between mice and human beings.
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PMID:Serum withdrawal up-regulates human SIRT1 gene expression in a p53-dependent manner. 1926 81

A new type of small-molecular sirtuin inhibitor was designed on the basis of the proposed catalytic mechanism for deacetylation of acetylated lysine substrates by sirtuins. Among the compounds thus designed and synthesized, we found that 2k, which contains an ethoxycarbonyl group at the alpha position to the acetamide of acetylated lysine substrate analogue 1, showed potent inhibitory activity in an in vitro assay using recombinant SIRT1, with high selectivity over SIRT2 and SIRT3. Mechanistic study by means of kinetic analysis, mass spectroscopy, and computation indicated that the enol form of compound 2k nucleophilically attacks NAD(+) in the active site of SIRTs to afford the stable compound 2k-ADP-ribose conjugate 5, leading to inhibition of the enzyme activity. Compound 2k also caused a dose-dependent increase of p53 acetylation in human colon cancer HCT116 cells, indicating inhibition of SIRT1 in the cells. These results have implications for the development of selective sirtuin inhibitors by means of mechanism-based drug design.
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PMID:Inhibition of human sirtuins by in situ generation of an acetylated lysine-ADP-ribose conjugate. 1941 17

Sirtuins are the class III histone deacetylases that catalyze the deacetylation of acetyl-lysine residues of histones and other proteins using nicotinamide adenine dinucleotide (NAD(+)) as the cofactor. The reaction yields the deacetylated protein, nicotinamide, and 2'-O-acetyl-ADP-ribose. Three 9-fluorenylmethoxycarbonyl (Fmoc)-labeled peptides derived from the amino acid sequence of p53, Fmoc-KK(Ac)-NH(2), Fmoc-KK(Ac)L-NH(2), and Fmoc-RHKK(Ac)-NH(2), were characterized as substrates for two of the human sirtuins: SIRT1 and SIRT2. The deacetylation was monitored by a validated capillary electrophoresis assay. Efficient deacetylation by SIRT1 and SIRT2 was demonstrated for all three peptide substrates. The kinetics of the enzymatic reaction was determined with the Michaelis constants (K(m)) varying between 16.7 and 34.6 microM for SIRT1 and between 34.7 and 58.6 microM for SIRT2. Resveratrol did not function as an activator for SIRT1 using the Fmoc-labeled peptides as SIRT substrates. The IC(50) values of sirtinol using the three peptide substrates were determined. Further sirtuin inhibitors were also evaluated.
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PMID:9-Fluorenylmethoxycarbonyl-labeled peptides as substrates in a capillary electrophoresis-based assay for sirtuin enzymes. 1945 28

SIRT1, an NAD(+) (nicotinamide adenine dinucleotide)-dependent deacetylase, protects cells from stress-induced apoptosis, and its orthologues delay aging in lower eukaryotes. SIRT1 increases survival in response to stress such as DNA damage by deacetylating a number of substrates including pro-apoptotic protein p53. The molecular mechanism by which DNA-damage activates SIRT1 is not known. By screening a kinase inhibitor library, we identified CK2 as a SIRT1 kinase. CK2 is a pleiotropic kinase with more than 300 substrates and well-known anti-apoptotic and pro-growth activities. We find that CK2 is recruited to SIRT1 after ionizing radiation (IR) and phosphorylates conserved residues Ser 154, 649, 651 and 683 in the N- and C-terminal domains of mouse SIRT1. Phosphorylation of SIRT1 increases its deacetylation rate but not if the four Ser residues are mutated. In addition, phosphorylation of SIRT1 increases its substrate-binding affinity. CK2-mediated phosphorylation increases the ability of SIRT1 to deacetylate p53 and protect cells from apoptosis after DNA damage. Based on these findings, we propose that CK2 protects against IR-induced apoptosis partly by phosphorylating and activating SIRT1. Thus, this work suggests that SIRT1 is a component of the expansive anti-apoptotic network controlled by CK2. Since expression of both CK2 and SIRT1 is upregulated with tumorigenesis and downregulated with senescence, the CK2-SIRT1 link sheds new light on how CK2 may regulate cancer development and aging.
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PMID:CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage. 1968 May 52


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