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Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1496-501. doi: 10.1073/pnas.0802674106. Epub 2009 Jan 21.

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span.

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1
Department of Pathology, Harvard Medical School, 77 Ave Louis Pasteur, Boston MA 02115, USA.

Abstract

CtBP (C-terminal binding protein) is an evolutionarily conserved NAD(H)-dependent transcriptional corepressor, whose activity has been shown to be regulated by the NAD/NADH ratio. Although recent studies have provided significant new insights into mechanisms by which CtBP regulates transcription, the biological function of CtBP remains incompletely understood. Here, we report that genetic inactivation of the Caenorhabditis elegans homolog, ctbp-1, results in life span extension, which is suppressed by reintroduction of the ctbp-1 genomic DNA encoding wild-type but not NAD(H)-binding defective CTBP-1 protein. We show that CTBP-1 possibly modulates aging through the insulin/IGF-1 signaling pathway, dependent on the forkhead transcription factor DAF-16, but independent of the NAD-dependent histone deacetylase SIR-2.1. Genome-wide microarray analysis identifies >200 potential CTBP-1 target genes. Importantly, RNAi inhibition of a putative triacylglycerol lipase gene lips-7(C09E8.2) but not another lipase suppresses the life span extension phenotype. Consistently, metabolic analysis shows that the triacylglycerol level is reduced in the ctbp-1 deletion mutant, which is restored to the wild-type level by RNAi inhibition of lips-7. Taken together, our data suggest that CTBP-1 controls life span probably through the regulation of lipid metabolism.

PMID:
19164523
PMCID:
PMC2635826
DOI:
10.1073/pnas.0802674106
[Indexed for MEDLINE]
Free PMC Article
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