Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression
Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression
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DOI：
10.1002/jcb.20199
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发表时间：
2004-09-01
影响因子：
4
通讯作者：
Prywes, R
中科院分区：
文献类型：
--
作者：
Cen, B;Selvaraj, A;Prywes, R
Myocardin，巨核细胞白血病-1（MKL 1）和MKL 2属于一个新定义的转录辅激活因子家族。所有三个家族成员都与血清应答因子（SRF）结合，并强烈激活具有SRF结合位点的启动子的转录。SRF是血清诱导即刻早期基因如c-fos和许多肌肉特异性基因表达所必需的。与在肌肉特异性基因表达中的作用一致，myocardin在心脏和平滑肌细胞中特异性表达，而MKL 1和2广泛表达。特别是已显示肌心素是平滑肌发育所需的，而MKL 1/2是诱导立即早期基因的RhoA信号传导途径所需的。SRF可被至少两个共激活因子家族p62 TCF和myocardin/MKL激活。这些因子与SRF的相同区域结合，使得它们的结合是相互排斥的。这提供了一种通过差异激活共激活因子的途径调节SRF靶基因的机制。RhoA通路似乎通过改变MKL 1与肌动蛋白的结合并导致MKL 1从细胞质易位到细胞核来激活MKL 1。然而，尚未在所有细胞类型中观察到心肌蛋白/MKL家族的这种激活机制，因此可能存在其他调节机制。特别是，观察到MKL 1的快速血清诱导磷酸化。该共激活因子家族的调控是理解SRF靶基因在肌细胞分化或生长因子诱导的细胞增殖期间如何被激活的关键。(C)2004 Wiley-Liss，Inc.
Myocardin, megakaryoblastic leukemia-1 (MKL1), and MKL2 belong to a newly defined family of transcriptional coactivators. All three family members bind to serum response factor (SRF) and strongly activate transcription from promoters with SRF binding sites. SRF is required for the serum induction of immediate early genes such as c-fos and for the expression of many muscle specific genes. Consistent with a role in muscle specific gene expression, myocardin is specifically expressed in cardiac and smooth muscle cells while MKL1 and 2 are broadly expressed. Myocardin has particularly been shown to be required for smooth muscle development while MKL1/2 are required for the RhoA signaling pathway for induction of immediate early genes. SRF can be activated by at least two families of coactivators, p62TCF and myocardin/MKL. These factors bind to the same region of SRF such that their binding is mutually exclusive. This provides one mechanism of regulation of SRF target genes by pathways that differentially activate the coactivators. The RhoA pathway appears to activate MKL1 by altering MKL1's binding to actin and causing MKL1's translocation from the cytoplasm to the nucleus. However, this mechanism of activation of the myocardin/MKL family has not been observed in all cell types such that other regulatory mechanism(s) likely exist. In particular, rapid serum inducible phosphorylation of MKL1 was observed. The regulation of this coactivator family is key to understanding how SRF target genes are activated during muscle cell differentiation or growth factor induced cell proliferation. (C) 2004 Wiley-Liss, Inc.