Cross-talk between glycogen synthase kinase 3β (GSK3β) and p38MAPK regulates myocyte enhancer factor 2 (MEF2) activity in skeletal and cardiac muscle
Cross-talk between glycogen synthase kinase 3β (GSK3β) and p38MAPK regulates myocyte enhancer factor 2 (MEF2) activity in skeletal and cardiac muscle
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DOI：
10.1016/j.yjmcc.2012.10.013
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发表时间：
2013-01-01
影响因子：
5
通讯作者：
McDermott, J. C.
中科院分区：
文献类型：
--
作者：
Dionyssiou, M. G.;Nowacki, N. B.;McDermott, J. C.
表征控制MEF 2转录因子的信号网络对于理解骨骼肌和心肌基因表达至关重要。糖原合成酶激酶3 β（GSK 3 β）通过p38 MAPK的相互调节间接调节MEF 2活性。GSK 3 β和p38 MAPK之间的相互作用调节骨骼肌和心肌中的MEF 2活性。了解在MEF 2控制汇聚的信号网络中的串扰在心脏和骨骼肌病理学中具有治疗意义。糖原合成酶激酶3 β（GSK 3 β）是抑制肌生成和心肌细胞肥大的横纹肌基因表达的已知调节剂。由于肌细胞增强因子2（MEF 2）蛋白是这两个系统中的关键转录调节因子，因此我们评估了MEF 2是否是GSK 3 β的靶点。GSK 3 β的药理学抑制导致骨骼肌成肌细胞和心肌细胞中MEF 2A/D表达和转录活性增强。尽管计算机模拟分析显示MEF 2A上的GSK 3 β共有（S/T）XXX（S/T）位点，但随后的体外激酶测定显示MEF 2A仅为弱底物。然而，我们确实观察到用GSK 3 β抑制剂处理的骨骼肌成肌细胞中MEF 2A的翻译后修饰，这与p38 MAPK磷酸化增加（一种有效的MEF 2A激活剂）一致，表明GSK 3 β抑制可能去抑制p38 MAPK。在小鼠中，心脏特异性切除GSK 3 β也导致p38 MAPK活性上调。有趣的是，在药理学p38 MAPK抑制（SB 203580）后，GSK 3 β抑制失去了其对MEF 2转录活性的影响，表明两种途径之间的有效串扰。因此，我们已经证明，p38 MAPK和GSK 3 β信号传导之间的串扰会聚在MEF 2活性上，对心脏和骨骼肌基因表达的治疗性调节具有潜在的后果。(c)2012爱思唯尔有限公司保留所有权利。
Characterizing the signaling network that controls MEF2 transcription factors is crucial for understanding skeletal and cardiac muscle gene expression. Glycogen synthase kinase 3 beta (GSK3 beta) regulates MEF2 activity indirectly through reciprocal regulation of p38MAPK. Cross-talk between GSK3 beta and p38MAPK regulates MEF2 activity in skeletal and cardiac muscle. Understanding cross-talk in the signaling network converging at MEF2 control has therapeutic implications in cardiac and skeletal muscle pathology. Glycogen synthase kinase 3 beta (GSK3 beta) is a known regulator of striated muscle gene expression suppressing both myogenesis and cardiomyocyte hypertrophy. Since myocyte enhancer factor 2 (MEF2) proteins are key transcriptional regulators in both systems, we assessed whether MEF2 is a target for GSK3 beta. Pharmacological inhibition of GSK3 beta resulted in enhanced MEF2A/D expression and transcriptional activity in skeletal myoblasts and cardiac myocytes. Even though in silico analysis revealed GSK3 beta consensus (S/T)XXX(S/T) sites on MEF2A, a subsequent in vitro kinase assay revealed that MEF2A is only a weak substrate. However, we did observe a post-translational modification in MEF2A in skeletal myoblasts treated with a GSK3 beta inhibitor which coincided with increased p38MAPK phosphorylation, a potent MEF2A activator, indicating that GSK3 beta inhibition may de-repress p38MAPK. Heart specific excision of GSK3 beta in mice also resulted in up-regulation of p38MAPK activity. Interestingly, upon pharmacological p38MAPK inhibition (SB203580), GSK3 beta inhibition loses its effect on MEF2 transcriptional activity suggesting potent cross-talk between the two pathways. Thus we have documented that cross-talk between p38MAPK and GSK3 beta signaling converges on MEF2 activity having potential consequences for therapeutic modulation of cardiac and skeletal muscle gene expression. (c) 2012 Elsevier Ltd. All rights reserved.