Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin
Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin
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DOI：
10.1016/j.devcel.2005.05.017
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发表时间：
2005-08-01
影响因子：
11.8
通讯作者：
Olson, EN
中科院分区：
文献类型：
--
作者：
Liu, ZP;Wang, ZG;Olson, EN
平滑肌细胞（SMC）在增殖和分化状态之间调节其表型以响应生理和病理线索。胰岛素样生长因子-1通过激活磷脂酰肌醇-3-激酶（PI 3 K）Akt信号通路刺激SMC分化。Foxo叉头转录因子作为Akt的下游靶标，并通过Akt磷酸化而失活。我们发现Foxo 4通过与平滑肌基因的转录辅激活因子myocardin相互作用并抑制其活性来抑制SMC分化。PI 3 K/Akt信号至少部分地通过刺激Foxo 4的核输出来促进SMC分化，从而从其抑制性影响中释放心肌蛋白。因此，通过siRNA减少SMC中Foxo 4的表达增强了心肌蛋白活性和SMC分化。我们的结论是信号依赖性的相互作用Foxo 4与myocardin夫妇细胞外信号与SMC分化的转录程序。
Smooth muscle cells (SMCs) modulate their phenotype between proliferative and differentiated states in response to physiological and pathological cues. Insulin-like growth factor-l 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.