Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4 - Implications in cardiac muscle gene regulation during hypertrophy
Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4 - Implications in cardiac muscle gene regulation during hypertrophy
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DOI：
10.1074/jbc.m209998200
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发表时间：
2003-05-30
影响因子：
4.8
通讯作者：
Gupta, MP
中科院分区：
文献类型：
--
作者：
Davis, FJ;Gupta, M;Gupta, MP
血清反应因子（SRF）在心肌细胞发育、肌肉基因转录和肥大中起关键作用。以前，细胞内Ca 2+水平的升高被证明激活SRF功能，而不涉及三级复杂因子的Ets家族通过未知的调节机制。在这里，我们测试的假设，即染色质重塑酶的II类组蛋白脱乙酰酶（HDAC 4）调节SRF活性在Ca 2+敏感的方式。HDAC 4的表达在肌肉和非肌肉细胞中都深刻地抑制了SRF介导的转录。蛋白质相互作用研究证明了HDAC 4与SRF在活细胞中的物理关联。SRF/HDAC 4共缔合通过用肥大激动剂如血管紧张素-II和Ca 2+离子载体离子霉素处理细胞而被破坏。此外，Ca 2 +/钙调蛋白依赖性蛋白激酶（CaMK）-IV的激活阻止SRF/HDAC 4相互作用和去抑制SRF依赖性转录活性。SRF.HDAC4复合物定位于细胞核，并且活化的CaMK-IV破坏HDAC 4/SRF缔合，导致HDAC 4从细胞核输出并刺激SRF转录活性。因此，这些结果将SRF鉴定为HDAC 4的功能性相互作用靶点，并定义了一种新的三级复杂因子独立的Ca 2 +/CaMK介导的信号转导激活SRF的机制。
Serum response factor (SRF) plays a pivotal role in cardiac myocyte development, muscle gene transcription, and hypertrophy. Previously, elevation of intracellular levels of Ca2+ was shown to activate SRF function without involving the Ets family of tertiary complex factors through an unknown regulatory mechanism. Here, we tested the hypothesis that the chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca2+-sensitive manner. Expression of HDAC4 profoundly repressed SRF-mediated transcription in both muscle and nonmuscle cells. Protein interaction studies demonstrated physical association of HDAC4 with SRF in living cells. The SRF/HDAC4 co-association was disrupted by treatment of cells with hypertrophic agonists such as angiotensin-II and a Ca2+ ionophore, ionomycin. Furthermore, activation of Ca2+/calmodulin-dependent protein kinase (CaMK)-IV prevented SRF/HDAC4 interaction and derepressed SRF-dependent transcription activity. The SRF.HDAC4 complex was localized to the cell nucleus, and the activated CaMK-IV disrupted HDAC4/SRF association, leading to export of HDAC4 from the nucleus and stimulation of SRF transcription activity. Thus, these results identify SRF as a functional interacting target of HDAC4 and define a novel tertiary complex factor-independent mechanism for SRF activation by Ca2+/CaMK-mediated signaling.