Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury
Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury
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DOI：
10.1523/jneurosci.2478-07.2007
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发表时间：
2007-08-01
影响因子：
5.3
通讯作者：
Yoon, Sung Ok
中科院分区：
文献类型：
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作者：
Li, Qi Ming;Tep, Chhavy;Yoon, Sung Ok
虽然少突胶质细胞在脊髓损伤后发生凋亡，但其死亡的分子机制尚不清楚。我们报告，少突胶质细胞凋亡是由c-Jun N-末端激酶3（JNK 3）和蛋白质相互作用的有丝分裂激酶，从来没有在有丝分裂AI（Pin 1），其行动收敛于髓细胞白血病序列-1（Mcl-1）。JNK 3在损伤后被激活，通过促进Mcl-1的降解诱导细胞色素c释放，Mcl-1的稳定性部分由Pin 1维持。Pin 1在其组成性磷酸化位点Thr（163）Pro结合Mcl-1，并通过抑制泛素化使其稳定。损伤后，JNK 3将Mcl-1磷酸化为Ser（121）Pro，促进Pin 1从Mcl-1上解离。JNK 3因此通过抵消Pin 1的保护性结合来诱导Mcl-1降解。这些结果通过在JNK 3（-/-）和Pin 1（-/-）小鼠之间观察到的相反表型得到证实：JNK 3（-/-）小鼠中少突胶质细胞凋亡和细胞色素c释放减少，但Pin 1（-/-）小鼠中升高。因此，本报告揭示了细胞色素c的释放是在JNK 3和Pin 1的相反控制下的机制，这两种调节剂的活性是复杂耦合的。
Although oligodendrocytes undergo apoptosis after spinal cord injury, molecular mechanisms responsible for their death have been unknown. We report that oligodendrocyte apoptosis is regulated oppositely by c-Jun N-terminal kinase 3 (JNK3) and protein interacting with the mitotic kinase, never in mitosis AI (Pin1), the actions of which converge on myeloid cell leukemia sequence-1 (Mcl-1). Activated after injury, JNK3 induces cytochrome c release by facilitating the degradation of Mcl-1, the stability of which is maintained in part by Pin1. Pin1 binds Mcl-1 at its constitutively phosphorylated site, Thr(163)Pro, and stabilizes it by inhibiting ubiquitination. After injury JNK3 phosphorylates Mcl-1 at Ser(121)Pro, facilitating the dissociation of Pin1 from Mcl-1. JNK3 thus induces Mcl-1 degradation by counteracting the protective binding of Pin1. These results are confirmed by the opposing phenotypes observed between JNK3(-/-) and Pin1(-/-) mice: oligodendrocyte apoptosis and cytochrome c release are reduced in JNK3(-/-) but elevated in Pin1(-/-) mice. This report thus unveils a mechanism by which cytochrome c release is under the opposite control of JNK3 and Pin1, regulators for which the activities are intricately coupled.