Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation.
Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation.
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DOI：
10.4161/auto.6788
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发表时间：
2008-10
期刊：
影响因子：
13.3
通讯作者：
Levine B
中科院分区：
文献类型：
--
作者：
Wei Y;Sinha S;Levine B
自噬和细胞凋亡都是受JNK介导的Bcl2磷酸化调控的基本细胞通路。几年前，JNK介导的Bcl2磷酸化干扰了其与Bax等促凋亡BH3结构域蛋白的结合，最近，我们的实验室发现JNK1介导的Bcl2磷酸化干扰了其与自噬BH3结构域蛋白Beclin 1的结合。在这里，我们研究了营养饥饿过程中Bcl2磷酸化、Bcl2/Beclin 1相互作用、Bcl2/Bax相互作用和caspase3激活之间的动力学关系。我们发现，在短时间的营养剥夺(4小时)后，少量的Bcl2磷酸化使Bcl2从Bcl2/Beclin 1复合体解离，但不从Bcl2/Bax复合体解离。在营养剥夺16小时后，细胞内Bcl2的磷酸化水平达到最高水平，Bcl2/Bax复合体被破坏，并检测到活性的caspase3，表明启动了细胞凋亡。基于这一结果，我们提出了一个推测模型，以了解JNK1介导的Bcl-2磷酸化调控自噬和细胞凋亡之间的相互关系。根据这一模型，最初可能发生快速的Bcl2磷酸化，通过破坏Bcl2/Beclin 1复合体和激活自噬来促进细胞存活。在某一时刻，当自噬不再能够维持细胞存活时，Bcl2的磷酸化可能会使其抗凋亡功能失活。
Autophagy and apoptosis are fundamental cellular pathways that are both regulated by JNK mediated Bcl-2 phosphorylation. Several years ago, JNK-mediated Bcl-2 phosphorylation was shown to interfere with its binding to pro-apoptotic BH3 domain-containing proteins such as Bax and recently, our laboratory demonstrated that JNK1-mediated Bcl-2 phosphorylation interferes with its binding to the pro-autophagy BH3 domain-containing protein Beclin 1. Here, we examined the kinetic relationship between Bcl-2 phosphorylation, Bcl-2/Beclin 1 interactions, Bcl-2/Bax interactions and caspase 3 activation during nutrient starvation. We found that after a short period of nutrient deprivation (4 hours), a small amount of Bcl-2 phosphorylation dissociates Bcl-2 from the Bcl-2/Beclin 1 complex but not from the Bcl-2/Bax complex. After 16 hours of nutrient deprivation, Bcl-2 phosphorylation reaches maximal levels, the Bcl-2/Bax complex is disrupted, and active caspase 3 is detected, indicating the initiation of apoptosis. Based on this result, we propose a speculative model for understanding the interrelationship between autophagy and apoptosis regulated by JNK1-mediated Bcl-2 phosphorylation. According to this model, rapid Bcl-2 phosphorylation may occur initially to promote cell survival by disrupting the Bcl-2/Beclin 1 complex and activating autophagy. At a certain point when autophagy is no longer able to keep the cell alive, Bcl-2 phosphorylation might then serve to inactivate its anti-apoptotic function.
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影响因子：
16
作者：
Ventura, JJ;H端bner, A;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
7.7
作者：
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Yoshimori, T
DOI：
10.1016/s0006-291x(03)00591-6
发表时间：
2003-05-02
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Levine, B
影响因子：
64.5
作者：
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通讯作者：
Levine, B