p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps
p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps
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DOI：
10.1128/mcb.20.11.3951-3964.2000
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发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Puri, PL
中科院分区：
文献类型：
--
作者：
Wu, ZG;Woodring, PJ;Puri, PL
细胞外信号通过丝裂原活化蛋白激酶（MAPK）传递到细胞核，调节肌细胞生成。我们研究了两个MAPK，p38和细胞外信号调节激酶（ERK），其活动在肌肉分化过程中发生显着变化的作用。p38在诱导分化的肌细胞中被迅速激活。这种激活不同于由应激和细胞因子触发的激活，因为它与Jun-N-末端激酶刺激无关，并且在肌管形成的整个过程中维持。此外，p38的激活是独立的一个平行的促肌生成途径刺激胰岛素样生长因子1。抑制p38阻止肌原细胞系和人原代肌细胞的分化程序。相反，故意激活内源性p38刺激肌肉分化，即使在存在的抗生肌线索。许多证据表明p38是MyoD的激活剂：（i）p38激酶活性是MyoD应答基因表达所需的，（ii）p38的强制诱导刺激Gal 4-MyoD融合蛋白的转录活性，并允许MyoD有效激活染色质整合的报告基因，和（iii）在源自p38 α（-/-）胚胎的小鼠胚胎成纤维细胞中，MyoD依赖性肌原性转化减少。p38的激活还通过直接磷酸化增强了肌细胞增强子结合因子2A（MEF 2A）和MEF 2C的转录活性。对于MEF 2C，一个残基（Thr 293）的选择性磷酸化是分化肌细胞中的组织特异性激活信号。最后，ERK显示出双相激活曲线，在未分化的成肌细胞和有丝分裂后的肌管中具有活性峰值。重要的是，ERK的激活抑制成肌细胞中的肌原性转录，但有助于肌原性转录的激活并调节有丝分裂后反应（即，肥大性生长）。
The extracellular signals which regulate the myogenic program are transduced to the nucleus by mitogen-activated protein kinases (MAPKs). We have investigated the role of two MAPKs, p38 and extracellular signal-regulated kinase (ERK), whose activities undergo significant changes during muscle differentiation. p38 is rapidly activated in myocytes induced to differentiate. This activation differs from those triggered by stress and cytokines, because it is not linked to Jun-N-terminal kinase stimulation and is maintained during the whole process of myotube formation. Moreover, p38 activation is independent of a parallel promyogenic pathway stimulated by insulin-like growth factor 1. Inhibition of p38 prevents the differentiation program in myogenic cell lines and human primary myocytes. Conversely, deliberate activation of endogenous p38 stimulates muscle differentiation even in the presence of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-responsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of chromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic conversion is reduced in mouse embryonic fibroblasts derived from p38 alpha(-/-) embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ERK shows a biphasic activation profile, with peaks of activity in undifferentiated myoblasts and postmitotic myotubes. Importantly, activation of ERK is inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic responses (i.e., hypertrophic growth) in myotubes.