A non-apoptotic role for caspase-9 in muscle differentiation
A non-apoptotic role for caspase-9 in muscle differentiation
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DOI：
10.1242/jcs.024547
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发表时间：
2008-11-15
影响因子：
4
通讯作者：
Fearnhead, Howard O.
中科院分区：
文献类型：
--
作者：
Murray, Thomas V. A.;McMahon, Jill M.;Fearnhead, Howard O.
胱天蛋白酶是半胱氨酸蛋白酶的一个家族，最常研究其在细胞凋亡中的作用，也已被证明具有对有效执行细胞分化至关重要的功能。已经描述的一个这样的作用是要求胱天蛋白酶-3用于骨骼肌成肌细胞分化成肌管，但是，到目前为止，在这种情况下导致胱天蛋白酶-3活化的机制仍然是难以捉摸的。在这里，我们证明，caspase-9，在线粒体死亡途径的启动caspase，是负责caspase-3的活化分化C2 C12细胞。使用短发夹RNA构建体降低caspase-9水平，可以阻止caspase-3激活并抑制成肌细胞融合。肌球蛋白重链的表达，伴随成肌细胞分化，是不依赖半胱天冬酶。Bcl-xL是一种抑制caspase-9活化的蛋白质，其过表达对肌肉分化具有与caspase-9敲低相同的作用。这些数据表明，分化需要线粒体途径;然而，不能检测到细胞色素c或Smac（Diablo）的释放，这提高了在肌肉分化期间半胱天冬酶-9活化的新机制的可能性。
Caspases, a family of cysteine proteases most often investigated for their roles in apoptosis, have also been demonstrated to have functions that are vital for the efficient execution of cell differentiation. One such role that has been described is the requirement of caspase-3 for the differentiation of skeletal myoblasts into myotubes but, as yet, the mechanism leading to caspase-3 activation in this case remains elusive. Here, we demonstrate that caspase-9, an initiator caspase in the mitochondrial death pathway, is responsible for the activation of caspase-3 in differentiating C2C12 cells. Reduction of caspase-9 levels, using an shRNA construct, prevented caspase-3 activation and inhibited myoblast fusion. Myosin-heavy-chain expression, which accompanies myoblastic differentiation, was not caspase-dependent. Overexpression of Bcl-xL, a protein that inhibits caspase-9 activation, had the same effect on muscle differentiation as knockdown of caspase-9. These data suggest that the mitochondrial pathway is required for differentiation; however, the release of cytochrome c or Smac (Diablo) could not be detected, raising the possibility of a novel mechanism of caspase-9 activation during muscle differentiation.