Liu Zhi-Ping, Wang Zhigao, Yanagisawa Hiromi, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Dev Cell. 2005 Aug;9(2):261-70. doi: 10.1016/j.devcel.2005.05.017.
Smooth muscle cells (SMCs) modulate their phenotype between proliferative and differentiated states in response to physiological and pathological cues. Insulin-like growth factor-I stimulates differentiation of SMCs by activating phosphoinositide-3-kinase (PI3K)-Akt signaling. Foxo forkhead transcription factors act as downstream targets of Akt and are inactivated through phosphorylation by Akt. We show that Foxo4 represses SMC differentiation by interacting with and inhibiting the activity of myocardin, a transcriptional coactivator of smooth muscle genes. PI3K/Akt signaling promotes SMC differentiation, at least in part, by stimulating nuclear export of Foxo4, thereby releasing myocardin from its inhibitory influence. Accordingly, reduction of Foxo4 expression in SMCs by siRNA enhances myocardin activity and SMC differentiation. We conclude that signal-dependent interaction of Foxo4 with myocardin couples extracellular signals with the transcriptional program for SMC differentiation.
平滑肌细胞（SMCs）会根据生理和病理信号在增殖状态和分化状态之间调节其表型。胰岛素样生长因子-I通过激活磷酸肌醇-3-激酶（PI3K）-Akt信号传导来刺激平滑肌细胞的分化。Foxo叉头转录因子作为Akt的下游靶点，并通过Akt磷酸化而失活。我们发现，Foxo4通过与心肌素（一种平滑肌基因的转录共激活因子）相互作用并抑制其活性，从而抑制平滑肌细胞的分化。PI3K/Akt信号传导至少部分地通过刺激Foxo4的核输出，从而使心肌素摆脱其抑制性影响，来促进平滑肌细胞的分化。因此，通过小干扰RNA（siRNA）降低平滑肌细胞中Foxo4的表达可增强心肌素活性和平滑肌细胞的分化。我们得出结论，Foxo4与心肌素之间的信号依赖性相互作用将细胞外信号与平滑肌细胞分化的转录程序联系起来。
