FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1 gene expression.
Biochem Biophys Res Commun
; 337(4): 1092-6, 2005 Dec 02.
Article
em En
| MEDLINE
| ID: mdl-16236254
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
/
Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina
/
Sirtuínas
/
Fatores de Transcrição Forkhead
Limite:
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article