Department of Medicine, Veterans Affairs North Texas Health Care System, Dallas, TX 75216, USA.
J Biol Chem. 2012 Aug 31;287(36):30800-11. doi: 10.1074/jbc.M111.244780. Epub 2012 Jul 17.
Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors. HIF-1α plays a prominent role in hypoxic gene induction. HIF-2α target genes are more restricted but include erythropoietin (Epo), one of the most highly hypoxia-inducible genes in mammals. We previously reported that HIF-2α is acetylated during hypoxia but is rapidly deacetylated by the stress-responsive deacetylase Sirtuin 1. We now demonstrate that the lysine acetyltransferases cAMP-response element-binding protein-binding protein (CBP) and p300 are required for efficient Epo induction during hypoxia. However, despite close structural similarity, the roles of CBP and p300 differ in HIF signaling. CBP acetylates HIF-2α, is a major coactivator for HIF-2-mediated Epo induction, and is required for Sirt1 augmentation of HIF-2 signaling during hypoxia in Hep3B cells. In comparison, p300 is a major contributor for HIF-1 signaling as indicated by induction of Pgk1. Whereas CBP can bind with HIF-2α independent of the HIF-2α C-terminal activation domain via enzyme/substrate interactions, p300 only complexes with HIF-2α through the C-terminal activation domain. Maximal CBP/HIF-2 signaling requires intact CBP acetyltransferase activity in both Hep3B cells as well as in mice.
缺氧诱导因子 (HIFs) 是对氧敏感的转录因子。HIF-1α 在缺氧诱导基因表达中起重要作用。HIF-2α 的靶基因受到更多限制，但包括促红细胞生成素 (Epo)，这是哺乳动物中最受缺氧诱导的基因之一。我们之前报道过，HIF-2α 在缺氧时发生乙酰化，但很快被应激反应去乙酰化酶 Sirtuin 1 去乙酰化。我们现在证明，在缺氧期间，cAMP 反应元件结合蛋白结合蛋白 (CBP) 和 p300 等赖氨酸乙酰转移酶是 Epo 诱导所必需的。然而，尽管结构非常相似，CBP 和 p300 在 HIF 信号转导中的作用却不同。CBP 乙酰化 HIF-2α，是 HIF-2 介导的 Epo 诱导的主要共激活因子，并且是 Sirt1 增强 Hep3B 细胞缺氧时 HIF-2 信号所必需的。相比之下，p300 作为 HIF-1 信号的主要贡献者，如 Pgk1 的诱导所示。虽然 CBP 可以通过酶/底物相互作用与 HIF-2α 结合，而无需 HIF-2α C 末端激活结构域，但 p300 仅通过 C 末端激活结构域与 HIF-2α 形成复合物。在 Hep3B 细胞和小鼠中，最大的 CBP/HIF-2 信号需要完整的 CBP 乙酰转移酶活性。
