The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling
The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling
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DOI：
10.1126/science.1092880
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发表时间：
2004-02-27
期刊：
影响因子：
56.9
通讯作者：
Behrens, A
中科院分区：
文献类型：
--
作者：
Nateri, AS;Riera-Sans, L;Behrens, A
Jun N-末端激酶（JNK）是神经元微管组装和凋亡所必需的。激活蛋白1（AP 1）转录因子c-Jun在其反式激活结构域内的多个位点磷酸化是JNK诱导的神经毒性所必需的。我们报告说，在神经元中的c-Jun的稳定性是由E3连接酶SCFFbw 7，它泛素化磷酸化的c-Jun，促进c-Jun降解。Fbw 7耗竭导致磷酸化c-Jun的积累、AP 1活性的刺激和神经元凋亡。因此，SCFFbw 7拮抗JNK信号传导的凋亡c-Jun依赖性效应臂，允许神经元耐受潜在的神经毒性JNK活性。
Jun N-terminal kinases (JNKs) are essential for neuronal microtubule assembly and apoptosis. Phosphorylation of the activating protein 1 (AP1) transcription factor c-Jun, at multiple sites within its transactivation domain, is required for JNK-induced neurotoxicity. We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCFFbw7, which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation. Fbw7 depletion resulted in accumulation of phosphorylated c-Jun, stimulation of AP1 activity, and neuronal apoptosis. SCFFbw7 therefore antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling, allowing neurons to tolerate potentially neurotoxic JNK activity.