Erythropoietin-activated ERK/MAP kinase enhances GATA-4 acetylation via phosphorylation of serine 261 of GATA-4
Erythropoietin-activated ERK/MAP kinase enhances GATA-4 acetylation via phosphorylation of serine 261 of GATA-4
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DOI：
10.1002/jcp.24121
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发表时间：
2013-01-01
影响因子：
5.6
通讯作者：
Kwak, Young-Lan
中科院分区：
文献类型：
--
作者：
Jun, Ji Hae;Shim, Jae-Kwang;Kwak, Young-Lan
GATA-4是一种锌指转录因子，在心脏发育中起着关键作用。先前的研究表明，p300靶向的GATA-4乙酰化增加了GATA-4的稳定性和转录活性，从而刺激心肌细胞肥厚。促红细胞生成素（EPO）是一种缺氧诱导的正常红细胞生成所必需的激素，已知可对缺血性或非缺血性心脏病发挥心脏保护作用。虽然EPO在病变心脏中的作用机制多种多样，但其在正常情况下的作用机制尚未被研究。在本研究中，我们旨在探讨epo诱导的ERK信号传导对GATA-4蛋白作用调控的影响。EPO处理通过ERK信号通路增加内源性GATA-4蛋白水平。U0126抑制ERK活性，抑制epo诱导的大鼠心肌细胞GATA-4蛋白表达。此外，在P19细胞中，通过过表达组成型活性MEK1激活ERK，强烈增加GATA-4磷酸化，随后增强其乙酰化。epo诱导的ERK活化进一步增加了GATA-4与p300的关联。另一方面，使用siRNA敲除p300可减少erk诱导的GATA-4乙酰化。由于epo通过ERK信号通路诱导GATA-4磷酸化与GATA-4乙酰化直接相关，因此我们研究了GATA-4中ERK依赖性磷酸化位点。位点定向突变提示GATA-4中的Ser-261在erk介导的GATA-4乙酰化中起重要作用。综上所述，这些结果表明，epo诱导的ERK信号激活增加了GATA-4的磷酸化和乙酰化，部分原因是GATA-4和p300之间的关联增加，而这些过程需要GATA-4 Ser-261残基的磷酸化。j .细胞。物理学报，28(2):391 - 391,2013。(c) 2012 Wiley期刊有限公司
GATA-4, a zinc finger transcription factor, plays a critical role in heart development. Previous studies have shown that p300-targeted GATA-4 acetylation increases GATA-4 stability and transcriptional activity, which then stimulates hypertrophy of cardiomyocyte. Erythropoietin (EPO), an essential hypoxia-induced hormone for normal erythropoiesis, is known to exert cardioprotective effects against heart disease of either ischemic or non-ischemic origins. Although, various action mechanisms of EPO have been proposed in the diseased heart, its action mechanism in normal condition has not been investigated. In this study, we aimed to investigate the influence of EPO-induced ERK signaling on the regulation of GATA-4 protein action. EPO treatment increased the protein level of endogenous GATA-4 via ERK signaling pathway. Inhibition of ERK activity by U0126, suppressed EPO-induced expression of GATA-4 protein in rat cardiac myocytes. In addition, ERK activation by over-expression of constitutively active MEK1 strongly increased GATA-4 phosphorylation and subsequently enhanced its acetylation in P19 cells. EPO-induced ERK activation further increased the association of GATA-4 with p300. On the other hand, knock-down of p300 using siRNA diminished ERK-induced GATA-4 acetylation. As EPO-induced GATA-4 phosphorylation via ERK signaling pathway directly correlated with GATA-4 acetylation, we investigated to identify the ERK-dependent phosphorylation sites in GATA-4. Site-directed mutagenesis implicated that Ser-261 in GATA-4 played an important role for ERK-mediated GATA-4 acetylation. Taken together, these results indicated that EPO-induced ERK signaling activation increased GATA-4 phosphorylation and acetylation, partly via increase in the association between GATA-4 and p300, and these processes required the phosphorylation of GATA-4 at Ser-261 residue. J. Cell. Physiol. 228: 190197, 2013. (c) 2012 Wiley Periodicals, Inc.