Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo
Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo
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DOI：
10.1073/pnas.1104499108
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发表时间：
2011-07-26
影响因子：
11.1
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
van Berlo, Jop H.;Elrod, John W.;Molkentin, Jeffery D.
心肌肥厚是一种对应激刺激或损伤做出反应的适应性生长过程，在此过程中诱导多条信号转导通路，最终导致转录因子激活和基因表达的重新编程。GATA4是心脏中的一个关键转录因子，已知通过接收MAPK信号来诱导/调节肥大程序。在这里，我们产生了敲打小鼠，在其中，Gata4中一个已知的丝氨酸105(S105)处的MAPK磷酸化位点被突变为丙氨酸。纯合的Gata4-S105A突变小鼠成年后仍可存活，尽管它们表现出心肌的应激反应受损。例如，在Gata4-S105A小鼠中，注射苯肾上腺素激动剂2wk时的心肌肥大反应明显减弱，在施加刺激1和2wk时对压力超负荷的肥大反应也是如此。Gata4-S105A小鼠在压力超负荷2周后也更容易发生心力衰竭和心脏扩张。在上游通路方面，Gata4-S105A小鼠的心脏在体内使用激活的MEK1转基因基因直接激活ERK1/2后不能有效地肥大。从机制上讲，这些心脏中的GATA4突变蛋白未能显示出对肥大刺激的DNA结合增强。此外，来自Gata4-S105A小鼠的心脏在肥大诱导基因、胎儿基因和重塑相关基因的表达方面发生了显著变化。
Cardiac hypertrophy is an adaptive growth process that occurs in response to stress stimulation or injury wherein multiple signal transduction pathways are induced, culminating in transcription factor activation and the reprogramming of gene expression. GATA4 is a critical transcription factor in the heart that is known to induce/regulate the hypertrophic program, in part, by receiving signals from MAPKs. Here we generated knock-in mice in which a known MAPK phosphorylation site at serine 105 (S105) in Gata4 that augments activity was mutated to alanine. Homozygous Gata4-S105A mutant mice were viable as adults, although they showed a compromised stress response of the myocardium. For example, cardiac hypertrophy in response to phenylephrine agonist infusion for 2 wk was largely blunted in Gata4-S105A mice, as was the hypertrophic response to pressure overload at 1 and 2 wk of applied stimulation. Gata4-S105A mice were also more susceptible to heart failure and cardiac dilation after 2 wk of pressure overload. With respect to the upstream pathway, hearts from Gata4-S105A mice did not efficiently hypertrophy following direct ERK1/2 activation using an activated MEK1 transgene in vivo. Mechanistically, GATA4 mutant protein from these hearts failed to show enhanced DNA binding in response to hypertrophic stimulation. Moreover, hearts from Gata4-S105A mice had significant changes in the expression of hypertrophy-inducible, fetal, and remodeling-related genes.