Inhibition of transcriptional activity of c-JUN by SIRT1.
c-JUN is a major component of heterodimer transcription factor AP-1 (Activator Protein-1) that activates gene transcription in cell proliferation, inflammation and stress responses. SIRT1 (Sirtuin 1) is a histone deacetylase that controls gene transcription through modification of chromatin structure. However, it is not clear if SIRT1 regulates c-JUN activity in the control of gene transcription. Here, we show that SIRT1 associated with c-JUN in co-immunoprecipitation of whole cell lysate, and inhibited the transcriptional activity of c-JUN in the mammalian two hybridization system. SIRT1 was found in the AP-1 response element in the matrix metalloproteinase-9 (MMP9) promoter DNA leading to inhibition of histone 3 acetylation as shown in a ChIP assay. The SIRT1 signal was reduced by the AP-1 activator PMA, and induced by the SIRT1 activator Resveratrol in the promoter DNA. SIRT1-mediaetd inhibition of AP-1 was demonstrated in the MMP9 gene expression at the gene promoter, mRNA and protein levels. In mouse embryonic fibroblast (MEF) with SIRT1 deficiency (SIRT1(-/-)), mRNA and protein of MMP9 were increased in the basal condition, and the inhibitory activity of Resveratrol was significantly attenuated. Glucose-induced MMP9 expression was also inhibited by SIRT1 in response to Resveratrol. These data consistently suggest that SIRT1 directly inhibits the transcriptional activity of AP-1 by targeting c-JUN.
Gao
Zhanguo
Z
Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
Ye
Jianping
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D020798:Two-Hybrid System Techniques
D000975:Antioxidants; D016755:Proto-Oncogene Proteins c-jun; D013267:Stilbenes; D020780:Matrix Metalloproteinase 9; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol