FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1 gene expression.
Sirtuin 1 (SirT1), an NAD-dependent deacetylase that is important for promoting longevity during caloric restriction, can deacetylate and enhance the function of forkhead box transcription factors, O subfamily (FoxO). We examined the effect of SirT1 on the regulation of insulin-like growth factor-binding protein 1 (IGFBP-1), a known target of FoxO proteins that is increased in fasting. Co-transfection with a SirT1 expression vector dose-dependently stimulated IGFBP-1 promoter activity and a heterologous reporter gene construct containing three FoxO-binding sites linked to a minimal promoter. This effect is mimicked by 20muM resveratrol, a potent SirT1 activator, and immunoprecipitation and Western blotting confirm that SirT1 and FoxO1 interact in cells. Interestingly, mutation of FoxO-binding sites in the IGFBP-1 promoter reduces, but does not completely disrupt, the stimulatory effect of SirT1 on promoter activity. We found that overexpression of SirT1 is accompanied by enhanced mitogen-activated protein kinase (MAPK) activation. Treatment of SirT1-cotransfected cells with PD98059, which inhibits MAPK activation, decreased IGFBP-1 promoter activity by approximately 50%, in a FoxO-binding site-independent manner, and disrupts the residual effect of SirT1. These results indicate that SirT1 stimulates IGFBP-1 promoter activity through FoxO-dependent and -independent mechanisms, and provides the first evidence that activation of MAPK contributes to effects of SirT1 on gene expression.
Gan
Lixia
L
Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, Que., Canada H4H 1R3.
Han
Yingshan
Y
Bastianetto
Stephane
S
Dumont
Yvan
Y
Unterman
Terry G
TG
Quirion
Remi
R
D001483:Base Sequence; D002460:Cell Line; D051858:Forkhead Transcription Factors / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
D051858:Forkhead Transcription Factors; D018970:Insulin-Like Growth Factor Binding Protein 1; D037761:Sirtuins