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PMID:20042607

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Citation

Zhang, R, Chen, HZ, Liu, JJ, Jia, YY, Zhang, ZQ, Yang, RF, Zhang, Y, Xu, J, Wei, YS, Liu, DP and Liang, CC (2010) SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J. Biol. Chem. 285:7097-110

Abstract

SIRT1 (Sirtuin type 1), a mammalian orthologue of yeast SIR2 (silent information regulator 2), has been shown to mediate a variety of calorie restriction (CR)-induced physiological events, such as cell fate regulation via deacetylation of the substrate proteins. However, whether SIRT1 deacetylates activator protein-1 (AP-1) to influence its transcriptional activity and target gene expression is still unknown. Here we demonstrate that SIRT1 directly interacts with the basic leucine zipper domains of c-Fos and c-Jun, the major components of AP-1, by which SIRT1 suppressed the transcriptional activity of AP-1. This process requires the deacetylase activity of SIRT1. Notably, SIRT1 reduced the expression of COX-2, a typical AP-1 target gene, and decreased prostaglandin E(2) (PGE(2)) production of peritoneal macrophages (pMPhis). pMPhis with SIRT1 overexpression displayed improved phagocytosis and tumoricidal functions, which are associated with depressed PGE(2). Furthermore, SIRT1 protein level was up-regulated in CR mouse pMPhis, whereas elevated SIRT1 decreased COX-2 expression and improved PGE(2)-related macrophage functions that were reversed following inhibition of SIRT1 deacetylase activity. Thus, our results indicate that SIRT1 may be a mediator of CR-induced macrophage regulation, and its deacetylase activity contributes to the inhibition of AP-1 transcriptional activity and COX-2 expression leading to amelioration of macrophage function.

Links

PubMed PMC2844159 Online version:10.1074/jbc.M109.038604

Keywords

Animals; Caloric Restriction; Cell Line; Cyclooxygenase 2/genetics; Cyclooxygenase 2/metabolism; Gene Expression Regulation; Humans; Leucine Zippers; Macrophages/cytology; Macrophages/physiology; Male; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins c-fos/chemistry; Proto-Oncogene Proteins c-fos/genetics; Proto-Oncogene Proteins c-fos/metabolism; Proto-Oncogene Proteins c-jun/chemistry; Proto-Oncogene Proteins c-jun/genetics; Proto-Oncogene Proteins c-jun/metabolism; Random Allocation; Sirtuin 1/genetics; Sirtuin 1/metabolism; Transcription Factor AP-1/genetics; Transcription Factor AP-1/metabolism; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SIRT1

involved_in

GO:2000111: positive regulation of macrophage apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIRT1

involved_in

GO:0031393: negative regulation of prostaglandin biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIR1

involved_in

GO:0031393: negative regulation of prostaglandin biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIR1

involved_in

GO:2000111: positive regulation of macrophage apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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