FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1 gene expression
FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1 gene expression
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DOI：
10.1016/j.bbrc.2005.09.169
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发表时间：
2005-12-02
影响因子：
3.1
通讯作者：
Quirion, R
中科院分区：
文献类型：
--
作者：
Gan, LX;Han, YS;Quirion, R
Sirtum 1（SirT 1）是一种NAD依赖性脱乙酰酶，能使叉头盒转录因子0亚家族（FoxO）脱乙酰化并增强其功能，在热量限制期间对促进长寿起重要作用。我们研究了SirT 1对胰岛素样生长因子结合蛋白1（IGFBP-1）的调节作用，IGFBP-1是FoxO蛋白的一个已知靶点，在禁食时增加。共转染SirT 1表达载体剂量依赖性刺激IGFBP-1启动子活性和异源报告基因构建体含有三个FoxO结合位点连接到一个最小的启动子。20 μ M白藜芦醇（一种有效的SirT 1激活剂）模拟了这种效应，免疫沉淀和Western印迹证实了SirT 1和FoxO 1在细胞中相互作用。有趣的是，IGFBP-1启动子中FoxO结合位点的突变降低了SirT 1对启动子活性的刺激作用，但没有完全破坏。我们发现SirT 1的过度表达伴随着丝裂原活化蛋白激酶（MAPK）激活的增强。用PD 98059（抑制MAPK活化）处理SirT 1共转染细胞，以FoxO结合位点非依赖性方式降低IGFBP-1启动子活性约50%，并破坏SirT 1的残余效应。这些结果表明，SirT 1刺激IGFBP-1启动子活性通过FoxO依赖和非依赖机制，并提供了第一个证据，MAPK的激活有助于SirT 1对基因表达的影响。(c)2005年爱思唯尔公司All rights reserved.
Sirtum 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, 0 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 20 mu M 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 similar to 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. (c) 2005 Elsevier Inc. All rights reserved.