Tzivion Guri, Dobson Melissa, Ramakrishnan Gopalakrishnan
Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Biochim Biophys Acta. 2011 Nov;1813(11):1938-45. doi: 10.1016/j.bbamcr.2011.06.002. Epub 2011 Jun 17.
The forkhead box O (FoxO) transcription factor family is a key player in an evolutionary conserved pathway downstream of insulin and insulin-like growth factor receptors. The mammalian FoxO family consists of FoxO1, 3, 4 and 6, which share high similarity in their structure, function and regulation. FoxO proteins are involved in diverse cellular and physiological processes including cell proliferation, apoptosis, reactive oxygen species (ROS) response, longevity, cancer and regulation of cell cycle and metabolism. The regulation of FoxO protein function involves an intricate network of posttranslational modifications and protein-protein interactions that provide integrated cellular response to changing physiological conditions and cues. AKT was identified in early genetic and biochemical studies as a main regulator of FoxO function in diverse organisms. Though other FoxO regulatory pathways and mechanisms have been delineated since, AKT remains a key regulator of the pathway. The present review summarizes the current knowledge of FoxO regulation by AKT and 14-3-3 proteins, focusing on its mechanistic and structural aspects and discusses its crosstalk with the other FoxO regulatory mechanisms. This article is part of a Special Issue entitled: PI3K-AKT-FoxO axis in cancer and aging.
叉头框O（FoxO）转录因子家族是胰岛素和胰岛素样生长因子受体下游进化保守通路中的关键参与者。哺乳动物的FoxO家族由FoxO1、3、4和6组成，它们在结构、功能和调控方面具有高度相似性。FoxO蛋白参与多种细胞和生理过程，包括细胞增殖、凋亡、活性氧（ROS）反应、寿命、癌症以及细胞周期和代谢的调控。FoxO蛋白功能的调控涉及一个复杂的翻译后修饰和蛋白质-蛋白质相互作用网络，该网络能使细胞对不断变化的生理条件和信号做出综合反应。在早期的遗传学和生物化学研究中，AKT被确定为多种生物体中FoxO功能的主要调节因子。尽管此后已经阐明了其他FoxO调节途径和机制，但AKT仍然是该途径的关键调节因子。本综述总结了目前关于AKT和14-3-3蛋白对FoxO调节的认识，重点关注其机制和结构方面，并讨论了它与其他FoxO调节机制的相互作用。本文是名为“癌症与衰老中的PI3K-AKT-FoxO轴”的特刊的一部分。
