Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.
NF-kappaB 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-kappaB. 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-kappaB 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-kappaB-regulated gene expression and sensitization of cells to TNFalpha-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 TNFalpha by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein.
Yeung
Fan
F
Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA 22908, USA.
Hoberg
Jamie E
JE
Ramsey
Catherine S
CS
Keller
Michael D
MD
Jones
David R
DR
Frye
Roy A
RA
Mayo
Marty W
MW
D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D017931:DNA Primers; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D016328:NF-kappa B; D013267:Stilbenes; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases; D000077185:Resveratrol