Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD
Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD
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DOI：
10.1126/science.284.5412.339
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发表时间：
1999-04-09
期刊：
影响因子：
56.9
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Wang, HG;Pathan, N;Reed, JC
钙激活蛋白磷酸酶钙调磷酸酶诱导细胞凋亡，但其机制尚不清楚。发现钙调磷酸酶使BAD（Bcl-2家族的促凋亡成员）去磷酸化，从而增强BAD与Bcl-x（L）的异源二聚化并促进凋亡。Ca ~（2+）诱导的BAD去磷酸化与其在胞浆中从14-3-3解离并转运到Bcl-x（L）所在的线粒体有关。在海马神经元中，L-谷氨酸，Ca 2+内流和钙调磷酸酶激活的诱导剂，触发线粒体靶向BAD和细胞凋亡，这两者都可以通过钙调磷酸酶的显性抑制突变体或这种磷酸酶的药理学抑制剂的共表达来抑制。因此，细胞凋亡诱导的Ca 2+诱导机制通过调节BAD磷酸化和细胞定位来起作用。
The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-x(L) and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-x(L) resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and Localization in cells.