Negative regulation of the deacetylase SIRT1 by DBC1.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Author(s): Zhao W;Zhao W; Kruse JP; Tang Y; Jung SY; Qin J; Gu W
  • Source:
    Nature [Nature] 2008 Jan 31; Vol. 451 (7178), pp. 587-90.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
    • Publication Information:
      Publication: Basingstoke : Nature Publishing Group
      Original Publication: London, Macmillan Journals ltd.
    • Subject Terms:
      Adaptor Proteins, Signal Transducing/*metabolism ; Sirtuins/*antagonists & inhibitors ; Sirtuins/*metabolism; Acetylation ; Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/genetics ; Apoptosis ; Cell Line, Tumor ; Humans ; Immunoprecipitation ; Protein Binding ; RNA Interference ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Sirtuin 1 ; Sirtuins/deficiency ; Sirtuins/genetics ; Transcriptional Activation ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation
    • Abstract:
      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.
    • References:
      Cell. 2006 Dec 15;127(6):1109-22. (PMID: 17112576)
      EMBO J. 2004 Jun 16;23(12):2369-80. (PMID: 15152190)
      Nat Rev Mol Cell Biol. 2005 Apr;6(4):298-305. (PMID: 15768047)
      Cell Metab. 2005 Sep;2(3):153-63. (PMID: 16154098)
      Dev Cell. 2005 Nov;9(5):605-15. (PMID: 16256736)
      Cell. 2001 Oct 19;107(2):137-48. (PMID: 11672522)
      Mol Cell. 2003 Feb;11(2):437-44. (PMID: 12620231)
      J Med Chem. 2005 Dec 1;48(24):7789-95. (PMID: 16302818)
      Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10794-9. (PMID: 12960381)
      Nature. 2000 Nov 16;408(6810):377-81. (PMID: 11099047)
      Cell. 1997 Aug 22;90(4):595-606. (PMID: 9288740)
      Cell. 2004 Feb 20;116(4):551-63. (PMID: 14980222)
      Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13647-52. (PMID: 12370419)
      PLoS Genet. 2005 Dec;1(6):e77. (PMID: 16362078)
      Nature. 2003 Sep 11;425(6954):191-6. (PMID: 12939617)
      Novartis Found Symp. 2004;259:208-17; discussion 218-25. (PMID: 15171256)
      Science. 2004 Mar 26;303(5666):2011-5. (PMID: 14976264)
      Genome Biol. 2004;5(5):224. (PMID: 15128440)
      Mol Cell. 2004 Mar 12;13(5):627-38. (PMID: 15023334)
      Cell. 2005 Nov 4;123(3):437-48. (PMID: 16269335)
      Nat Rev Drug Discov. 2006 Jun;5(6):493-506. (PMID: 16732220)
      Cell. 2001 Oct 19;107(2):149-59. (PMID: 11672523)
      Oncogene. 2005 Jul 21;24(31):4908-20. (PMID: 15824730)
      Cancer Lett. 2005 Jul 8;225(1):121-30. (PMID: 15922864)
      J Biol Chem. 2005 Apr 29;280(17):17038-45. (PMID: 15684413)
      Nature. 2006 Nov 16;444(7117):337-42. (PMID: 17086191)
      Cancer Res. 2006 Apr 15;66(8):4368-77. (PMID: 16618762)
      Nature. 2005 Mar 3;434(7029):113-8. (PMID: 15744310)
      EMBO J. 2002 May 15;21(10):2383-96. (PMID: 12006491)
      J Biol Chem. 2005 Apr 29;280(17):17187-95. (PMID: 15749705)
    • Grant Information:
      R01 CA085533 United States CA NCI NIH HHS; R01 CA098821 United States CA NCI NIH HHS; R01 CA098821-06A1 United States CA NCI NIH HHS
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (CCAR2 protein, human)
      0 (RNA, Small Interfering)
      0 (TP53 protein, human)
      0 (Tumor Suppressor Protein p53)
      EC 3.5.1.- (SIRT1 protein, human)
      EC 3.5.1.- (Sirtuin 1)
      EC 3.5.1.- (Sirtuins)
    • Publication Date:
      Date Created: 20080201 Date Completed: 20080305 Latest Revision: 20220408
    • Publication Date:
      20240829
    • Accession Number:
      PMC2866287
    • Accession Number:
      10.1038/nature06515
    • Accession Number:
      18235502