FOXOs转录因子生物学功能的研究进展

FOX家族是一组结构高度保守的转录因子,其功能及分子机制已逐步成为免疫学、遗传学、医学以及肿瘤学领域的研究热点。FOX蛋白家族有19个亚族,FOXOs是FOX家族的重要成员,其包含FOXO1、FOXO3a、FOXO4以及FOXO6四种转录因子,分别表达于不同的组织器官。FOXOs与细胞发育及代谢密切相关,参与氧化应激、DNA修复、细胞周期调控、细胞凋亡与自噬等众多细胞生理过程,在癌症、骨质疏松、心血管疾病、神经组织退化等多种年龄相关性疾病的发生及发展过程中也发挥着重要的作用,对其功能及分子调控机制的研究可为防治年龄相关性疾病提供新的思路。本文就FOXO家族的活性调节及其在细胞氧化应激、细胞周期及凋亡方面的最新进展做一综述。     

The Acetate/ACSS2 Switch Regulates HIF-2 Stress Signaling in the Tumor Cell Microenvironment

Optimal stress signaling by Hypoxia Inducible Factor 2 (HIF-2) during low oxygen states or hypoxia requires coupled actions of a specific coactivator/lysine acetyltransferase, Creb binding protein (CBP), and a specific deacetylase, Sirtuin 1 (SIRT1). We recently reported that acetylation of HIF-2 by CBP also requires a specific acetyl CoA generator, acetate-dependent acetyl CoA synthetase 2 (ACSS2). In this study, we demonstrate that ACSS2/HIF-2 signaling is active not only during hypoxia, but also during glucose deprivation. Acetate levels increase during stress and coincide with maximal HIF-2α acetylation and CBP/HIF-2α complex formation. Exogenous acetate induces HIF-2α acetylation, CBP/HIF-2α complex formation, and HIF-2 signaling. ACSS2 and HIF-2 are required for maximal colony formation, proliferation, migration, and invasion during stress. Acetate also stimulates flank tumor growth and metastasis in mice in an ACSS2 and HIF-2 dependent manner. Thus, ACSS2/CBP/SIRT1/HIF-2 signaling links nutrient sensing and stress signaling with cancer growth and progression in mammals.