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Gene Review

SIRT1  -  sirtuin 1

Homo sapiens

Synonyms: NAD-dependent protein deacetylase sirtuin-1, Regulatory protein SIR2 homolog 1, SIR2-like protein 1, SIR2L1, hSIR2, ...
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Disease relevance of SIRT1

  • Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neuroblastoma cells and post-mitotic rat primary hippocampal and cerebellar granule neurons [1].
  • SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling [2].
  • Tat and SIRT1 coimmunoprecipitate and synergistically activate the HIV promoter [3].
  • DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins [4].
  • We propose that low expression of SIRT1 and Foxo1 leads to impaired Foxo1-C/EBPalpha complex formation, which contributes to the diminished adiponectin expression in obesity and type 2 diabetes [5].
  • In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival [6].
  • HIC-1, which has been shown to regulate SIRT1 levels, was markedly reduced in the same tumors, suggesting that a reduction in HIC-1 may be in part responsible for the increased expression of SIRT1 in prostatic adenocarcinomas [7].
  • Collectively, these findings identify SIRT1 as a corepressor of AR and elucidate a new molecular pathway relevant to prostate cancer growth and approaches to therapy [8].
  • SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001) [9].

Psychiatry related information on SIRT1


High impact information on SIRT1

  • Studies by and now show that resveratrol promotes longevity and improves glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the transcriptional coactivator PGC-1alpha [11].
  • Inhibition of SIRT1 function in cells without HIC1 abolishes the resistance to apoptosis [12].
  • Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses [12].
  • Since aging increases promoter hypermethylation and epigenetic silencing of HIC1, we speculate that the resultant upregulation of SIRT1 may be a double-edged sword that both promotes survival of aging cells and increases cancer risk in mammals [12].
  • SIRT1 might increase longevity by shifting FOXO dependent responses away from cell death and towards cell survival [13].

Chemical compound and disease context of SIRT1


Biological context of SIRT1


Anatomical context of SIRT1


Associations of SIRT1 with chemical compounds

  • Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications [22].
  • We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group [23].
  • The upregulation of SIRT mRNAs was inhibited by actinomycin D [1].
  • Studies involving cobB, a bacterial SIR2-like gene, have suggested it could encode a pyridine nucleotide transferase [24].
  • Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation [25].
  • AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose [26].
  • In the mitochondrial fraction, SIRT1 inhibition by siRNA for SIRT1 increased the amount of Bax but reduced the amount of Bcl-2, while resveratrol reduced the amount of Bax but increased the amount of Bcl-2 [27].

Physical interactions of SIRT1

  • SIRT1 was found to interact directly with BCL11A and was recruited to the promoter template in a BCL11A-dependent manner leading to transcriptional repression [28].
  • Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed [23].
  • SIRT1 binds and deacetylates the AR at a conserved lysine motif [4].
  • In contrast, mammalian SIRT1 was found to bind to FOXO4, catalyze its deacetylation in an NAD-dependent manner, and thereby increase its transactivation activity [29].
  • AROS was unable to cooperate in p53 inactivation in an AROS-binding-defective SIRT1 mutant [30].
  • SIRT1 interacts with LXR and promotes deacetylation and subsequent ubiquitination [31].

Regulatory relationships of SIRT1

  • Furthermore, NDRG1 expression was regulated by the activity of SIRT1 (Sir2-like protein 1), which promotes cell survival [32].
  • Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation [22].
  • EX-527 and TSA acted synergistically to increase acetyl-p53 levels, confirming that p53 acetylation is regulated by both SIRT1 and HDACs [18].
  • Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappaB signaling stimulated by Abeta and had strong neuroprotective effects [2].
  • We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity [33].

Other interactions of SIRT1

  • Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2 [16].
  • These findings define a role for SIRT1 in transcriptional repression mediated by BCL11A in mammalian cells [28].
  • Here we demonstrate that the human Sir2 homologue, SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo [34].
  • Interestingly, SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity [35].
  • Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1 [23].
  • Our results provide a possible molecular mechanism connecting the effects of CR on the endothelium and vascular tone to SIRT1-mediated deacetylation of eNOS [36].

Analytical, diagnostic and therapeutic context of SIRT1


  1. Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases. Kyrylenko, S., Kyrylenko, O., Suuronen, T., Salminen, A. Cell. Mol. Life Sci. (2003) [Pubmed]
  2. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L.F., Kwon, H., Yi, S., Mucke, L., Gan, L. J. Biol. Chem. (2005) [Pubmed]
  3. SIRT1 regulates HIV transcription via Tat deacetylation. Pagans, S., Pedal, A., North, B.J., Kaehlcke, K., Marshall, B.L., Dorr, A., Hetzer-Egger, C., Henklein, P., Frye, R., McBurney, M.W., Hruby, H., Jung, M., Verdin, E., Ott, M. PLoS Biol. (2005) [Pubmed]
  4. Hormonal Control of Androgen Receptor Function through SIRT1. Fu, M., Liu, M., Sauve, A.A., Jiao, X., Zhang, X., Wu, X., Powell, M.J., Yang, T., Gu, W., Avantaggiati, M.L., Pattabiraman, N., Pestell, T.G., Wang, F., Quong, A.A., Wang, C., Pestell, R.G. Mol. Cell. Biol. (2006) [Pubmed]
  5. SIRT1 Regulates Adiponectin Gene Expression through Foxo1-C/Enhancer-binding Protein {alpha} Transcriptional Complex. Qiao, L., Shao, J. J. Biol. Chem. (2006) [Pubmed]
  6. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. Kim, D., Nguyen, M.D., Dobbin, M.M., Fischer, A., Sananbenesi, F., Rodgers, J.T., Delalle, I., Baur, J.A., Sui, G., Armour, S.M., Puigserver, P., Sinclair, D.A., Tsai, L.H. EMBO J. (2007) [Pubmed]
  7. SIRT1 is significantly elevated in mouse and human prostate cancer. Huffman, D.M., Grizzle, W.E., Bamman, M.M., Kim, J.S., Eltoum, I.A., Elgavish, A., Nagy, T.R. Cancer Res. (2007) [Pubmed]
  8. Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. Dai, Y., Ngo, D., Forman, L.W., Qin, D.C., Jacob, J., Faller, D.V. Mol. Endocrinol. (2007) [Pubmed]
  9. Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma. Cha, E.J., Noh, S.J., Kwon, K.S., Kim, C.Y., Park, B.H., Park, H.S., Lee, H., Chung, M.J., Kang, M.J., Lee, D.G., Moon, W.S., Jang, K.Y. Clin. Cancer Res. (2009) [Pubmed]
  10. Resveratrol--a boon for treating Alzheimer's disease? Anekonda, T.S. Brain Res. Brain Res. Rev. (2006) [Pubmed]
  11. In vino veritas: a tale of two sirt1s? Koo, S.H., Montminy, M. Cell (2006) [Pubmed]
  12. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Chen, W.Y., Wang, D.H., Yen, R.C., Luo, J., Gu, W., Baylin, S.B. Cell (2005) [Pubmed]
  13. The interaction between FOXO and SIRT1: tipping the balance towards survival. Giannakou, M.E., Partridge, L. Trends Cell Biol. (2004) [Pubmed]
  14. Roles of SIRT1 and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma A375-S2 cell death. Wang, C., Wang, M.W., Tashiro, S., Onodera, S., Ikejima, T. J. Pharmacol. Sci. (2005) [Pubmed]
  15. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. Langley, E., Pearson, M., Faretta, M., Bauer, U.M., Frye, R.A., Minucci, S., Pelicci, P.G., Kouzarides, T. EMBO J. (2002) [Pubmed]
  16. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Heltweg, B., Gatbonton, T., Schuler, A.D., Posakony, J., Li, H., Goehle, S., Kollipara, R., Depinho, R.A., Gu, Y., Simon, J.A., Bedalov, A. Cancer Res. (2006) [Pubmed]
  17. Fluorescence assay of SIRT protein deacetylases using an acetylated peptide substrate and a secondary trypsin reaction. Marcotte, P.A., Richardson, P.L., Richardson, P.R., Guo, J., Barrett, L.W., Xu, N., Gunasekera, A., Glaser, K.B. Anal. Biochem. (2004) [Pubmed]
  18. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Solomon, J.M., Pasupuleti, R., Xu, L., McDonagh, T., Curtis, R., DiStefano, P.S., Huber, L.J. Mol. Cell. Biol. (2006) [Pubmed]
  19. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Ford, J., Jiang, M., Milner, J. Cancer Res. (2005) [Pubmed]
  20. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. Nemoto, S., Fergusson, M.M., Finkel, T. J. Biol. Chem. (2005) [Pubmed]
  21. Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation. Kume, S., Haneda, M., Kanasaki, K., Sugimoto, T., Araki, S., Isono, M., Isshiki, K., Uzu, T., Kashiwagi, A., Koya, D. Free Radic. Biol. Med. (2006) [Pubmed]
  22. Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Zhao, X., Sternsdorf, T., Bolger, T.A., Evans, R.M., Yao, T.P. Mol. Cell. Biol. (2005) [Pubmed]
  23. Mechanism of human SIRT1 activation by resveratrol. Borra, M.T., Smith, B.C., Denu, J.M. J. Biol. Chem. (2005) [Pubmed]
  24. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Frye, R.A. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  25. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Rodgers, J.T., Puigserver, P. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  26. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. Hou, X., Xu, S., Maitland-Toolan, K.A., Sato, K., Jiang, B., Ido, Y., Lan, F., Walsh, K., Wierzbicki, M., Verbeuren, T.J., Cohen, R.A., Zang, M. J. Biol. Chem. (2008) [Pubmed]
  27. SIRT1 regulation of apoptosis of human chondrocytes. Takayama, K., Ishida, K., Matsushita, T., Fujita, N., Hayashi, S., Sasaki, K., Tei, K., Kubo, S., Matsumoto, T., Fujioka, H., Kurosaka, M., Kuroda, R. Arthritis Rheum. (2009) [Pubmed]
  28. BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression. Senawong, T., Peterson, V.J., Leid, M. Arch. Biochem. Biophys. (2005) [Pubmed]
  29. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Kobayashi, Y., Furukawa-Hibi, Y., Chen, C., Horio, Y., Isobe, K., Ikeda, K., Motoyama, N. Int. J. Mol. Med. (2005) [Pubmed]
  30. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Kim, E.J., Kho, J.H., Kang, M.R., Um, S.J. Mol. Cell (2007) [Pubmed]
  31. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Li, X., Zhang, S., Blander, G., Tse, J.G., Krieger, M., Guarente, L. Mol. Cell (2007) [Pubmed]
  32. N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury. Chen, B., Nelson, D.M., Sadovsky, Y. J. Biol. Chem. (2006) [Pubmed]
  33. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., Hu, L.S., Cheng, H.L., Jedrychowski, M.P., Gygi, S.P., Sinclair, D.A., Alt, F.W., Greenberg, M.E. Science (2004) [Pubmed]
  34. Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression. Takata, T., Ishikawa, F. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  35. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. Yang, Y., Hou, H., Haller, E.M., Nicosia, S.V., Bai, W. EMBO J. (2005) [Pubmed]
  36. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Mattagajasingh, I., Kim, C.S., Naqvi, A., Yamamori, T., Hoffman, T.A., Jung, S.B., DeRicco, J., Kasuno, K., Irani, K. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  37. SIRT1 top 40 hits: use of one-bead, one-compound acetyl-peptide libraries and quantum dots to probe deacetylase specificity. Garske, A.L., Denu, J.M. Biochemistry (2006) [Pubmed]
  38. A defect in the activity of Delta6 and Delta5 desaturases may be a factor predisposing to the development of insulin resistance syndrome. Das, U.N. Prostaglandins Leukot. Essent. Fatty Acids (2005) [Pubmed]
  39. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1. Voelter-Mahlknecht, S., Mahlknecht, U. Int. J. Mol. Med. (2006) [Pubmed]
  40. Lung uptake of 201Tl in myocardial stress imaging: correlation with echocardiographic and scintigraphic variables of myocardial ischaemia. Chiti, A., Brambilla, M., Inglese, E., Tarolo, G.L. Nuclear medicine communications. (1995) [Pubmed]
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