Journal
EMBO JOURNAL
Volume 23, Issue 12, Pages 2369-2380Publisher
WILEY
DOI: 10.1038/sj.emboj.7600244
Keywords
apoptosis; cIAP-2 gene; RelA/p65; SIRTI; TNF alpha
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Funding
- NCI NIH HHS [K01CA78595, R01 CA095644, R01CA104397, CA-110552-01, R01CA095644, R01 CA104397, F32 CA110552] Funding Source: Medline
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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. SIRTI physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating ReIA/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 SIRTI is capable of protecting cells from p53-induced apoptosis, our work provides evidence that SIRTI activity augments apoptosis in response to TNFa by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein.
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