JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis
JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis
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DOI：
10.1016/s0896-6273(03)00355-6
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发表时间：
2003-06-19
期刊：
影响因子：
16.2
通讯作者：
Johnson, EM
中科院分区：
文献类型：
--
作者：
Putcha, GV;Le, SY;Johnson, EM
营养因子剥夺 (TFD) 激活 c-Jun N 末端激酶 (JNK)，最终导致 BH3 唯一的 BCL-2 蛋白 BIMEL 和 HRK 协调 AP1 依赖性反式激活，这反过来对于 BAX 依赖性细胞色素 c 释放、半胱天冬酶激活和细胞凋亡至关重要。在此，我们报道 TFD 不仅引起 BIMEL 的诱导，而且引起 BIMEL 的磷酸化。线粒体定位的 JNK 但不是上游激活剂，如混合谱系激酶 (MLK) 或丝裂原激活蛋白激酶激酶 (MKK)，在 Ser65 处特异性磷酸化 BIMEL，从而增强其促凋亡活性。抑制 JNK 通路可减弱 BIMEL 表达，阻止 BIMEL 磷酸化，并消除 TFD 诱导的细胞凋亡。相反，该通路的激活促进 BIMEL 表达和磷酸化，导致 BIM 和 BAX 依赖性细胞死亡。因此，JNK 在 TFD 过程中通过转录和翻译后调节 BIMEL 的促凋亡活性。
Trophic factor deprivation (TFD) activates c-Jun N-terminal kinases (JNKs), culminating in coordinate AP1- dependent transactivation of the BH3-only BCL-2 proteins BIMEL and HRK, which in turn are critical for BAX-dependent cytochrome c release, caspase activation, and apoptosis. Here, we report that TFD caused not only induction but also phosphorylation of BIMEL. Mitochondrially localized JNKs but not upstream activators, like mixed-lineage kinases (MLKs) or mitogen-activated protein kinase kinases (MKKs), specifically phosphorylated BIMEL at Ser65, potentiating its proapoptotic activity. Inhibition of the JNK pathway attenuated BIMEL expression, prevented BIMEL phosphorylation, and abrogated TFD-induced apoptosis. Conversely, activation of this pathway promoted BIMEL expression and phosphorylation, causing BIM- and BAX-dependent cell death. Thus, JNKs regulate the proapoptotic activity of BIMEL during TFD, both transcriptionally and posttranslationally.