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Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury.

http://www.ncbi.nlm.nih.gov/pubmed/17670986

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.

Pubmed ID: 17670986 RIS Download

Mesh terms: Animals | Apoptosis | Mice | Mice, Knockout | Mice, Transgenic | Mitogen-Activated Protein Kinase 10 | Oligodendroglia | Peptidylprolyl Isomerase | Spinal Cord Injuries | Ubiquitin

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Associated grants

  • Agency: NIA NIH HHS, Id: R01 AG022082
  • Agency: NINDS NIH HHS, Id: R01 NS 39472
  • Agency: NINDS NIH HHS, Id: R01 NS039472
  • Agency: NINDS NIH HHS, Id: R01 NS039472-04

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