Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SIRT1 is the mammalian homologue of yeast silent information regulator (Sir)-2, a member of the sirtuin family of protein deacetylases which have gained much attention as mediators of lifespan extension in several model organisms. Induction of SIRT1 expression also attenuates neuronal degeneration and death in animal models of Alzheimer's disease and Huntington's disease. SIRT1 induction, either by sirtuin activators such as resveratrol, or metabolic conditioning associated with caloric restriction (CR), could be neuroprotective in several ways. It could promote the non-amyloidogenic cleavage of the amyloid precursor protein, enhance clearance of amyloid beta-peptides, and reduced neuronal damage through potential inhibition of neuroinflammatory signaling pathways. In addition, increased SIRT1 activity could alter neuronal transcription profiles to enhance anti-stress and anti-apoptotic gene activities, and has been proposed to underlie the inhibition of axonal degeneration in the Wallerian degeneration slow (Wld(s)) phenotype. As neuronal degeneration is a major pathophysiological aspect of human aging, understanding the mechanism of SIRT1 neuroprotection promises novel strategies in clinical intervention of neurodegenerative diseases.
Mol Aspects Med 2008 Jun
PMID:SIRT1 and neuronal diseases. 1739 14

Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.
Mol Cell Biol 2007 Dec
PMID:Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. 1792 81

The NAD(+)-dependent deacetylase Sir2 regulates life span in lower eukaryotes. The mammalian ortholog SIRT1 regulates physiological processes including apoptosis, fat metabolism, glucose homeostasis, and neurodegeneration. Here we show that SIRT1 is a positive regulator of liver X receptor (LXR) proteins, nuclear receptors that function as cholesterol sensors and regulate whole-body cholesterol and lipid homeostasis. LXR acetylation is evident at a single conserved lysine (K432 in LXRalpha and K433 in LXRbeta) adjacent to the ligand-regulated activation domain AF2. SIRT1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRalpha by this sirtuin. Loss of SIRT1 in vivo reduces expression of a variety of LXR targets involved in lipid metabolism, including ABCA1, an ATP-binding cassette (ABC) transporter that mediates an early step of HDL biogenesis. Our findings suggest that deacetylation of LXRs by SIRT1 may be a mechanism that affects atherosclerosis and other aging-associated diseases.
Mol Cell 2007 Oct 12
PMID:SIRT1 deacetylates and positively regulates the nuclear receptor LXR. 1798 78

Sirtuins, homologs of the yeast SIR2 family, are protein deacetylases that require nicotinamide adenosine dinucleotide as cofactor. To determine whether the sirtuin family of deacetylases is involved in progesterone receptor (PR)-mediated transcription, the effect of sirtuin inhibitor, nicotinamide (NAM), was monitored in T47D breast cancer cells. NAM suppressed hormone-dependent activation of PR-regulated genes in a dose-dependent manner. Surprisingly, NAM-mediated inhibition of PR-mediated transcription occurs independently of SIRT1 and PARP1. Chromatin immunoprecipitation experiments did not show that PR binding nor that of the coactivators CBP and SRC3 was compromised. Consistent with the recruitment of the BRG1 chromatin remodeling complex, promoter chromatin remodeling still occurs despite NAM inhibition of PR transactivation. Rather, we show that this inhibition of transcription is due to dramatic loss of recruitment of the basal transcriptional machinery to the promoter. These results show that NAM uncouples promoter chromatin remodeling from transcription preinitiation complex assembly and suggest the existence of vital NAM-regulated steps required for promoter chromatin remodeling and basal transcription complex communication.
Mol Cell Biol 2008 Jan
PMID:Nicotinamide uncouples hormone-dependent chromatin remodeling from transcription complex assembly. 1795 62

Protein lysine deacetylases have a pivotal role in numerous biological processes and can be divided into the Rpd3/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3/Hda1 family contains 11 members, traditionally referred to as histone deacetylases (HDAC) 1-11, which are further grouped into classes I, II and IV. Whereas most class I HDACs are subunits of multiprotein nuclear complexes that are crucial for transcriptional repression and epigenetic landscaping, class II members regulate cytoplasmic processes or function as signal transducers that shuttle between the cytoplasm and the nucleus. Little is known about class IV HDAC11, although its evolutionary conservation implies a fundamental role in various organisms.
Nat Rev Mol Cell Biol 2008 Mar
PMID:The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. 1829 78

Oculopharyngeal muscular dystrophy (OPMD) is caused by polyalanine expansion in nuclear protein PABPN1 [poly(A) binding protein nuclear 1] and characterized by muscle degeneration. Druggable modifiers of proteotoxicity in degenerative diseases, notably the longevity modulators sirtuins, may constitute useful therapeutic targets. However, the modifiers of mutant PABPN1 are unknown. Here, we report that longevity and cell metabolism modifiers modulate mutant PABPN1 toxicity in the muscle cell. Using PABPN1 nematodes that show muscle cell degeneration and abnormal motility, we found that increased dosage of the sirtuin and deacetylase sir-2.1/SIRT1 exacerbated muscle pathology, an effect dependent on the transcription factor daf-16/FoxO and fuel sensor aak-2/AMPK (AMP-activated protein kinase), while null mutants of sir-2.1, daf-16 and aak-2 were protective. Consistently, the Sir2 inhibitor sirtinol was protective, whereas the Sir2 and AMPK activator resveratrol was detrimental. Furthermore, rescue by sirtinol was dependent on daf-16 and not aak-2, whereas aggravation by resveratrol was dependent on aak-2 and not daf-16. Finally, the survival of mammalian cells expressing mutant PABPN1 was promoted by sirtinol and decreased by resveratrol. Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases.
Hum Mol Genet 2008 Jul 15
PMID:Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1. 1839 76

There is an ever-increasing scientific interest for the interplay between cell's environment and the aging process. Although it is known that calorie restriction affects longevity, the exact molecular mechanisms through which nutrients influence various cell signalling/modulators of lifespan remain a largely unresolved issue. Among nutrients, glucose constitutes an evolutionarily stable, precious metabolic fuel, which is catabolized through glycolytic pathway providing energy in the form of ATP and consuming NAD. Accumulating evidence shows that among the important regulators of aging process are autophagy, sirtuin activity and oxidative stress. In light of recent work indicating that glucose availability decreases lifespan whilst impaired glucose metabolism extends life expectancy, the present article deals with the potential role of glucose in the aging process by regulating--directly through its metabolism or indirectly through insulin secretion--autophagy, sirtuins as well as other modulators of aging like oxidative stress and advanced glycation end-products (AGEs).
J Cell Mol Med 2008 Aug
PMID:Could glucose be a proaging factor? 1840 54

There are seven SIRT isoforms in mammals, with diverse biological functions including gene regulation, metabolism, and apoptosis. Among them, SIRT3 is the only sirtuin whose increased expression has been shown to correlate with an extended life span in humans. In this study, we examined the role of SIRT3 in murine cardiomyocytes. We found that SIRT3 is a stress-responsive deacetylase and that its increased expression protects myocytes from genotoxic and oxidative stress-mediated cell death. We show that, like human SIRT3, mouse SIRT3 is expressed in two forms, a approximately 44-kDa long form and a approximately 28-kDa short form. Whereas the long form is localized in the mitochondria, nucleus, and cytoplasm, the short form is localized exclusively in the mitochondria of cardiomyocytes. During stress, SIRT3 levels are increased not only in mitochondria but also in the nuclei of cardiomyocytes. We also identified Ku70 as a new target of SIRT3. SIRT3 physically binds to Ku70 and deacetylates it, and this promotes interaction of Ku70 with the proapoptotic protein Bax. Thus, under stress conditions, increased expression of SIRT3 protects cardiomyocytes, in part by hindering the translocation of Bax to mitochondria. These studies underscore an essential role of SIRT3 in the survival of cardiomyocytes in stress situations.
Mol Cell Biol 2008 Oct
PMID:SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. 1871 Sep 44

Sirtuins comprise a unique class of nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases that target multiple protein substrates to execute diverse biological functions. These enzymes are key regulators of clinically important cellular and organismal processes, including metabolism, cell division and aging. The desire to understand the important determinants of human health and lifespan has resulted in a firestorm of work on the seven mammalian sirtuins in less than a decade. The implication of sirtuins in medically important areas such as diabetes, cancer, cardiovascular dysfunction and neurodegenerative disease has further catapulted them to a prominent status as potential targets for nutritional and therapeutic development. Here, we present a review of published results on sirtuin biology and its relevance to human disease.
Cell Mol Life Sci 2008 Dec
PMID:Biological and potential therapeutic roles of sirtuin deacetylases. 1882 Sep 96

The sirtuin family of class III histone deacetylases (HDACs) is named after their homology to yeast silent information regulator 2 (SIR2). SIR2 and its mammalian derivatives (SIRT1-7) play a central role in gene silencing, cell cycle, aging and metabolism. Here we reported cDNA cloning, chromosome mapping,expression and evolutional analysis of sirtuin genes in Sus scrofa (Tongcheng pig). Sequence analysis showed that porcine sirtuin genes contain 7 members designated SIRT1-7. Tissue distribution analysis indicated porcine sirtuin genes ubiquitously expressed but with the highest abundance in brain, spinal cord and genital tissue. In silico and radiation hybrid mapping analysis mapped porcine SIRT1-7 to the chromosomes 14q23,6q11-12, 2q29, 14q19, 7p12, 2q11, and 12p15, respectively. We also isolated and characterized genomic sequence of porcine SIRT1, which spaned a region of 31,834 bp comprising 9 exons ranging in size from 80 bpto 2121 bp. The 5' flanking genomic region preceding an open reading frame of SIRT1 has a TATA box, a small300 bp CpG island and several putative Sp1 and p53 transcription factor binding sites. Moreover, we isolated two novel splicing SIRT6 variants with 346 bp (variant 2) in-frame deletions from lung and 327 bp(variant 3) in-frame deletions from spleen and brain. This is the first systematic report of molecular cloning and characterization of sirtuin genes in pigs, which will be helpful for a better understanding of the physiological role of sirtuin proteins in pigs.
Comp Biochem Physiol B Biochem Mol Biol 2009 Aug
PMID:Molecular cloning and characterization of porcine sirtuin genes. 1938 81


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