Inhibiting myosin light chain kinase induces apoptosis in vitro and in vivo
Inhibiting myosin light chain kinase induces apoptosis in vitro and in vivo
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DOI：
10.1128/mcb.25.14.6259-6266.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
de Lanerolle, P
中科院分区：
文献类型：
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作者：
Fazal, F;Gu, LZ;de Lanerolle, P
先前的短期研究已将肌球蛋白 II (MLC20) 20 kDa 轻链磷酸化的增加与凋亡细胞中的起泡相关。我们发现，当细胞受到各种凋亡剂刺激时，MLC20 磷酸化的增加很快就会发生 MLC20 去磷酸化。 MLC20 去磷酸化不是细胞凋亡的结果，因为当用促凋亡剂刺激细胞或通过药物抑制肌球蛋白轻链激酶 (MLCK) 或通过显微注射 MLCK 抑制性抗体时，MLC20 去磷酸化先于 caspase 激活。此外，当抑制 MLCK 或用肿瘤坏死因子 α 处理细胞时，阻断 caspase 激活可增加细胞存活率。肌动蛋白丝解聚或细胞分离、细胞骨架不稳定的过程或抑制肌球蛋白 ATP 酶活性也会导致 MLC20 去磷酸化和细胞死亡。体内实验表明，抑制 MLCK 会增加小鼠体内凋亡细胞的数量并延缓乳腺癌细胞的生长。因此，MLC20去磷酸化发生在生理细胞死亡期间，并且延长的MLC20去磷酸化可以引发细胞凋亡。
Previous short-term studies have correlated an increase in the phosphorylation of the 20-kDa light chain of myosin II (MLC20) with blebbing in apoptotic cells. We have found that this increase in MLC20 phosphorylation is rapidly followed by MLC20 dephosphorylation when cells are stimulated with various apoptotic agents. MLC20 dephosphorylation is not a consequence of apoptosis because MLC20 dephosphorylation precedes caspase activation when cells are stimulated with a proapoptotic agent or when myosin light chain kinase (MLCK) is inhibited pharmacologically or by microinjecting an inhibitory antibody to MLCK. Moreover, blocking caspase activation increased cell survival when MLCK is inhibited or when cells are treated with tumor necrosis factor alpha. Depolymerizing actin filaments or detaching cells, processes that destabilize the cytoskeleton, or inhibiting myosin ATPase activity also resulted in MLC20 dephosphorylation and cell death. In vivo experiments showed that inhibiting MLCK increased the number of apoptotic cells and retarded the growth of mammary cancer cells in mice. Thus, MLC20 dephosphorylation occurs during physiological cell death and prolonged MLC20 dephosphorylation can trigger apoptosis.