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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.
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Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.

机译：沉默的信息调节剂2通过其去乙酰基酶活性增强Foxo1介导的转录。

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摘要

Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of Foxo1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1 at residues acetylated by cAMP-response element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27(kip1) in a deacetylase-activity-dependent manner. Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems.
机译：长寿调节基因包括Forkhead转录因子FOXO和NAD依赖性组蛋白脱乙酰基酶沉默信息调节剂2（Sir2）。遗传学研究表明，Sir2起到延长类脂秀丽隐杆线虫（Caenorhabditis elegans）寿命的作用，该途径位于类胰岛素信号传导途径的FOXO家族成员DAF-16的上游。然而，在Sir2介导的寿命中需要DAF-16活性的分子机制仍然未知。在这里，我们显示了小鼠DAF-16直系同源物Foxo1（也称为FKHR）的可逆乙酰化作用，可调节其反式激活功能。 cAMP反应元件结合蛋白（CREB）结合蛋白在K242，K245和K262残基处结合Foxo1并使其乙酰化，其修饰涉及Foxo1作为转录因子的减弱。相反，Sir2在被cAMP反应元件结合蛋白结合蛋白乙酰化的残基上使Foxo1结合并脱乙酰化。 Sir2被募集到包含胰岛素反应序列的启动子，并以脱乙酰基酶活性依赖性方式增加锰超氧化物歧化酶和p27（kip1）的表达。我们的发现将Foxo1确立为Sir2在哺乳动物系统中的直接功能靶标。

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