Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA
Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA
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DOI：
10.1101/gad.915701
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发表时间：
2001-10-15
影响因子：
10.5
通讯作者：
Nemer, M
中科院分区：
文献类型：
--
作者：
Charron, F;Tsimiklis, G;Nemer, M
rho样gtpase在肌动蛋白细胞骨架响应受体刺激的变化中发挥关键作用，并与转录激活、细胞生长调节和致癌转化有关。最近，RhoA在心脏收缩性和肥厚性心肌细胞生长的调节中的作用已被提出，但RhoA在心脏中的功能机制仍未明确。我们现在报道，转录因子GATA-4是心脏基因的关键调节因子，是RhoA信号传导的核介质，并参与心肌细胞中肌节组装的控制。RhoA和GATA-4在肥厚生长刺激下的肌肉组织重组中都是必不可少的，任何一种蛋白的过表达都足以诱导肌肉组织重组。与RhoA和GATA信号的趋同一致，RhoA通过p38 mapk依赖途径增强GATA-4的转录活性，该途径磷酸化GATA-4激活域，GATA结合位点介导RhoA靶心脏启动子的激活。此外，显性阴性的GATA-4蛋白可消除rhoa诱导的肌节重组。转录因子GATA-4在肌瘤重组和心脏基因调控中作为RhoA介质的鉴定为RhoA对转录和细胞重塑的影响提供了联系。
Rho-like GTPases play a pivotal role in the orchestration of changes in the actin cytoskeleton in response to receptor stimulation, and have been implicated in transcriptional activation, cell growth regulation, and oncogenic transformation. Recently, a role for RhoA in the regulation of cardiac contractility and hypertrophic cardiomyocyte growth has been suggested but the mechanisms underlying RhoA function in the heart remain undefined. We now report that transcription factor GATA-4, a key regulator of cardiac genes, is a nuclear mediator of RhoA signaling and is involved in the control of sarcomere assembly in cardiomyocytes. Both RhoA and GATA-4 are essential for sarcomeric reorganization in response to hypertrophic growth stimuli and overexpression of either protein is sufficient to induce sarcomeric reorganization. Consistent with convergence of RhoA and GATA signaling RhoA potentiates the transcriptional activity of GATA-4 via a p38 MAPK-dependent pathway that phosphorylates GATA-4 activation domains and GATA binding sites mediate RhoA activation of target cardiac promoters. Moreover, a dominant-negative GATA-4 protein abolishes RhoA-induced sarcomere reorganization. The identification of transcription factor GATA-4 as a RhoA mediator in sarcomere reorganization and cardiac gene regulation provides a link between RhoA effects on transcription and cell remodeling.