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The Journal of Neuroscience, August 1, 2007, 27(31):8395-8404; doi:10.1523/JNEUROSCI.2478-07.2007

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Development/Plasticity/Repair
Opposite Regulation of Oligodendrocyte Apoptosis by JNK3 and Pin1 after Spinal Cord Injury

Qi Ming Li,^1,3 * Chhavy Tep,^1,2 * Tae Y. Yune,¹ Xiao Zhen Zhou,⁴ Takafumi Uchida,⁵ Kun Ping Lu,⁴ and Sung Ok Yoon¹

¹Center for Molecular Neurobiology and Department of Molecular and Cellular Biochemistry, ²Ohio State Biochemistry Program, and ³Ohio State Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, Ohio 43210, ⁴Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, and ⁵Molecular Enzymology, Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, Sendai-shi 980-8576, Japan

Correspondence should be addressed to Dr. Sung Ok Yoon, Center for Molecular Neurobiology, 184 Rightmire Hall, The Ohio State University, 1060 Carmack Road, Columbus, OH 43210. Email: Yoon.84{at}osu.edu

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 A I (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, Thr¹⁶³Pro, and stabilizes it by inhibiting ubiquitination. After injury JNK3 phosphorylates Mcl-1 at Ser¹²¹Pro, 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.

Key words: JNK; apoptosis; knock-out mice; mitochondria; oligodendrocyte; signal transduction

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Received March 23, 2007; revised June 23, 2007; accepted June 26, 2007.

Correspondence should be addressed to Dr. Sung Ok Yoon, Center for Molecular Neurobiology, 184 Rightmire Hall, The Ohio State University, 1060 Carmack Road, Columbus, OH 43210. Email: Yoon.84{at}osu.edu

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