Calcineurin initiates skeletal muscle differentiation by activating MEF2 and MyoD
Calcineurin initiates skeletal muscle differentiation by activating MEF2 and MyoD
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DOI：
10.1046/j.1432-0436.2003.710303.x
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发表时间：
2003-04-01
期刊：
影响因子：
2.9
通讯作者：
Pavlath, GK
中科院分区：
文献类型：
--
作者：
Friday, BB;Mitchell, PO;Pavlath, GK
骨骼肌分化的特征是退出细胞周期、表达肌肉特异性基因、融合成多核细胞以及组装收缩装置。尽管许多关键调控元件已被确定，但启动分化过程的因素尚不清楚。钙依赖性磷酸酶钙调磷酸酶在肌发生早期发挥重要的调节作用，但钙调磷酸酶在分化过程中的下游效应器尚不清楚。在这里，我们发现钙和钙调神经磷酸酶在转录水平上调节肌细胞生成素基因的表达。肌生成素启动子包含两个必需元件；分别结合 MRF 和 MEF2 转录因子的 E-box 和富含 A/T 的元件。这两种元素都对钙和钙调神经磷酸酶有反应。在分化成肌细胞时，MyoD 是与肌生成素启动子 E-box 结合的主要 MRF 蛋白。 Calcineurin 通过降低 Id 抑制蛋白的表达来间接激活 MyoD，可能是通过下调 Egr-1 的表达（Id 转录的上游激活剂）来实现。这些结果表明，钙调神经磷酸酶通过激活 MEF2 和 MyoD 转录因子从而诱导肌细胞生成素表达来调节骨骼肌分化。
Skeletal muscle differentiation is characterized by withdrawal from the cell cycle, expression of muscle specific genes, fusion into multinucleated cells, and assembly of the contractile apparatus. Although many of the key regulatory elements have been identified, the factors that initiate the differentiation process are not well understood. The calcium-dependent phosphatase calcineurin plays an important regulatory role early in myogenesis, but the downstream effectors of calcineurin in differentiation are not known. Here, we show that calcium and calcineurin regulate expression of the myogenin gene at the level of transcription. The myogenin promoter contains two essential elements; an E-box and an A/T rich element that bind MRF and MEF2 transcription factors, respectively. Both of these elements are responsive to calcium and calcineurin. In differentiating myoblasts, MyoD is the major MRF protein that binds to the myogenin promoter E-box. Calcineurin activates MyoD indirectly by decreasing the expression of the Id inhibitory proteins, probably by down-regulating Egr-1 expression, an upstream activator of Id transcription. These results demonstrate that calcineurin regulates skeletal muscle differentiation by activating MEF2 and MyoD transcription factors leading to the induction of myogenin expression.