A critical role of neural-specific JNK3 for ischemic apoptosis.
c-Jun N-terminal kinase (JNK) signaling is an important contributor to stress-induced apoptosis, but it is unclear whether JNK and its isoforms (JNK1, JNK2, and JNK3) have distinct roles in cerebral ischemia. Here we show that JNK1 is the major isoform responsible for the high level of basal JNK activity in the brain. In contrast, targeted deletion of Jnk3 not only reduces the stress-induced JNK activity, but also protects mice from brain injury after cerebral ischemia-hypoxia. The downstream mechanism of JNK3-mediated apoptosis may include the induction of Bim and Fas and the mitochondrial release of cytochrome c. These results suggest that JNK3 is a potential target for neuroprotection therapies in stroke.
Kuan
Chia-Yi
CY
Department of Pediatrics, Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA. alex.kuan@chmcc.org
Whitmarsh
Alan J
AJ
Yang
Derek D
DD
Liao
Guanghong
G
Schloemer
Aryn J
AJ
Dong
Chen
C
Bao
Jue
J
Banasiak
Kenneth J
KJ
Haddad
Gabriel G
GG
Flavell
Richard A
RA
Davis
Roger J
RJ
Rakic
Pasko
P
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007511:Ischemia; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
D020033:Protein Isoforms; D012333:RNA, Messenger; D045304:Cytochromes c; D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; D010100:Oxygen