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Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase
Author(s) -
Yeung Fan,
Hoberg Jamie E,
Ramsey Catherine S,
Keller Michael D,
Jones David R,
Frye Roy A,
Mayo Marty W
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600244
Subject(s) - biology , sirtuin 1 , transactivation , gene silencing , sirtuin , histone deacetylase , transcription factor , p300 cbp transcription factors , microbiology and biotechnology , creb binding protein , histone deacetylase 5 , hdac4 , sap30 , cancer research , histone , acetylation , creb , biochemistry , histone acetyltransferases , downregulation and upregulation , gene
NF‐κB 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‐κB. 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‐κB 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‐κB‐regulated gene expression and sensitization of cells to TNFα‐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 TNFα by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein.