Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury.
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.
Center for Molecular Neurobiology and Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA.
Qi Ming
QM
Li
Chhavy
C
Tep
Tae Y
TY
Yune
Xiao Zhen
XZ
Zhou
Takafumi
T
Uchida
Kun Ping
KP
Lu
Sung Ok
SO
Yoon
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048057:Mitogen-Activated Protein Kinase 10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009836:Oligodendroglia / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000378:metabolism
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D025801:Ubiquitin; D048057:Mitogen-Activated Protein Kinase 10; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse