JIP1 regulates neuronal apoptosis in response to stress.
We examined if the relative expression of JNK-interacting protein 1 (JIP1) and phosphorylated c-Jun N-terminal kinase (JNK) regulates cell signaling and contributes to selective neuronal vulnerability in response to environmental stress. In clonal neuroblastoma cultures, stresses such as hypoxia, ischemia, Abeta peptides, and UV irradiation rapidly reduced JIP1 expression. JIP1 mRNA expression was also down-regulated by UV stress and was accompanied by increased JNK and c-Jun activation and cell death. JIP1 protein reduction was partially reversed both by inhibitors predominantly of caspase 3 and of the JNK pathway and resulted in significantly increased cell survival. Conversely, overexpression of JIP1 decreased both nuclear translocation of activated-JNK, and c-Jun phosphorylation induced by either UV irradiation, or the JNK upstream activators, MKK7 or MEKK1. Cell death was reduced about 50% compared to GFP-transfected controls. JIP1 overexpression did not facilitate either JNK expression or activation. In the normal, non-stressed human hippocampus and rat hippocampal organotypic cultures, JIP1 and JNK3 were inversely expressed with more JIP1 in CA2 and CA3 and less in CA1 neurons. In the human hippocampus, transient hypoxia/ischemia selectively spares neurons in CA2 and CA3 and induces death of neurons in the hippocampal CA1 subregion. In the cultures, ischemia reduced JIP1 expression and activated JNK, c-Jun, and caspase 3. Inhibitors of the JNK pathway, JNK activation directly and of caspase 3 activation each partially reversed these effects. Thus, under certain stress conditions, down-regulation of JIP1 expression makes neurons more susceptible to apoptosis, suggesting JIP may serve as an anti-apoptosis factor.
Dong
Zhaohui
Z
Department of Pathology, Keck School of Medicine, USC, MCA-341A, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Zhou
Li
L
Del Villar
Keith
K
Ghanevati
Mahin
M
Tashjian
Vartan
V
Miller
Carol A
CA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D051379:Mice; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism* / Q000528:radiation effects; D009924:Organ Culture Techniques; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000473:pathology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014466:Ultraviolet Rays / Q000009:adverse effects
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D007211:Indoles; C490666:MAPK8IP1 protein, human; D016755:Proto-Oncogene Proteins c-jun; C007293:DAPI; D048057:Mitogen-Activated Protein Kinase 10; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases