Article
- The EMBO Journal (2004) 23, 2369 - 2380
- doi:10.1038/sj.emboj.7600244
Published online: 20 May 2004
Subject Categories:
Modulation of NF-
B-dependent transcription and cell survival by the SIRT1 deacetylase
Fan Yeung1, Jamie E Hoberg1, Catherine S Ramsey1, Michael D Keller1, David R Jones2, Roy A Frye3 and Marty W Mayo1,2
- Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA
- Department of Surgery, The University of Virginia, Charlottesville, VA, USA
- VA Medical Center, Pittsburgh, PA, USA
Correspondence to:
Marty W Mayo, Department of Biochemistry and Molecular Genetics, Box 800733, Jordan Hall/RM 6233, University of Virginia, Charlottesville, VA 22908, USA. Tel.: +1 434 924 2509; Fax: +1 434 982 1026; E-mail: mwm3y@virginia.edu
Received 12 February 2004; Accepted 30 April 2004
Abstract
NF-
B is responsible for upregulating gene products that control cell survival. In this study, we demonstrate that SIRT1, a nicotinamide adenosine dinucleotide-dependent histone deacetylase, regulates the transcriptional activity of NF-B. SIRT1, the mammalian ortholog of the yeast SIR2 (Silencing Information Regulator) and a member of the Sirtuin family, has been implicated in modulating transcriptional silencing and cell survival. SIRT1 physically interacts with the RelA/p65 subunit of NF-B and inhibits transcription by deacetylating RelA/p65 at lysine 310. Treatment of cells with resveratrol, a small-molecule agonist of Sirtuin activity, potentiates chromatin-associated SIRT1 protein on the cIAP-2 promoter region, an effect that correlates with a loss of NF-B-regulated gene expression and sensitization of cells to TNF
-induced apoptosis. While SIRT1 is capable of protecting cells from p53-induced apoptosis, our work provides evidence that SIRT1 activity augments apoptosis in response to TNF by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein.
Keywords:
- apoptosis,
- cIAP-2 gene,
- RelA/p65,
- SIRT1,
- TNF
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