Wang Jun, Li AnKang, Wang ZhiGao, Feng XinHua, Olson Eric N, Schwartz Robert J
The Institute of Biosciences and Technology, The Texas A&M University Health Science Center, 2121 W. Holcombe, Houston, TX 77030, USA.
Mol Cell Biol. 2007 Jan;27(2):622-32. doi: 10.1128/MCB.01160-06. Epub 2006 Nov 13.
Myocardin, a serum response factor (SRF)-dependent cofactor, is a potent activator of smooth muscle gene activity but a poor activator of cardiogenic genes in pluripotent 10T1/2 fibroblasts. Posttranslational modification of GATA4, another myocardin cofactor, by sumoylation strongly activated cardiogenic gene activity. Here, we found that myocardin's activity was strongly enhanced by SUMO-1 via modification of a lysine residue primarily located at position 445 and that the conversion of this residue to arginine (K445R) impaired myocardin transactivation. PIAS1 was involved in governing myocardin activity via its E3 ligase activity that stimulated myocardin sumoylation on an atypical sumoylation site(s) and by its physical association with myocardin. Myocardin initiated the expression of cardiac muscle-specified genes, such as those encoding cardiac alpha-actin and alpha-myosin heavy chain, in an SRF-dependent manner in 10T1/2 fibroblasts, but only in the presence of coexpressed SUMO-1/PIAS1. Thus, SUMO modification acted as a molecular switch to promote myocardin's role in cardiogenic gene expression.
心肌素是一种依赖血清反应因子（SRF）的辅因子，是平滑肌基因活性的强效激活剂，但在多能10T1/2成纤维细胞中对心脏发生基因的激活作用较弱。另一种心肌素辅因子GATA4经SUMO化的翻译后修饰强烈激活了心脏发生基因的活性。在此，我们发现SUMO-1通过修饰主要位于第445位的赖氨酸残基，强烈增强了心肌素的活性，并且将该残基转化为精氨酸（K445R）会损害心肌素的反式激活作用。PIAS1通过其E3连接酶活性参与调控心肌素活性，该活性刺激心肌素在非典型SUMO化位点进行SUMO化，并通过其与心肌素的物理结合来实现。心肌素以SRF依赖的方式在10T1/2成纤维细胞中启动心肌特异性基因的表达，例如那些编码心肌α-肌动蛋白和α-肌球蛋白重链的基因，但仅在共表达SUMO-1/PIAS1的情况下才会启动。因此，SUMO修饰作为一种分子开关，促进了心肌素在心脏发生基因表达中的作用。
