C-jun N-terminal kinase regulates the interaction between 14-3-3 and Bad in ethanol-induced cell death.
Activation of the c-jun N-terminal kinase (JNK) is known to be an important step during ethanol-induced cell death, but it has yet to be identified how JNK regulates apoptosis. Therefore, we investigated the mechanism by which JNK induces cell death following ethanol treatment. Ethanol (6 g/kg, 20% in saline) was administered subcutaneously to postnatal 7 day rat pups. Twelve hours after the first ethanol administration, rat pups were decapitated, and extracts of total protein from cerebral cortices were prepared. Ethanol exposure induced phosphorylation of JNK but did not affect the expression levels of pro- and antiapoptotic proteins. Furthermore, interactions of phospho-JNK (p-JNK) with 14-3-3 as well as with Bad were enhanced in the cerebral cortices of ethanol-treated rats. Pretreatment with JNK inhibitor (SP600125) of SH-SY5Y cells inhibited JNK phosphorylation and interaction between p-JNK and 14-3-3 resulting from ethanol. Furthermore, 14-3-3 interaction with Bad was diminished in the cerebral cortices of ethanol-treated rats. These findings suggest that JNK induces Bad release from 14-3-3 by inhibiting their interaction. After this event, Bad binds to Bcl-xL, releasing Bax from Bcl-xL and leading to cell death. We hypothesize that JNK may play an important role during ethanol-induced cell death via the inhibition of antiapoptotic function of 14-3-3 as well as activation of proapoptotic function of Bad.
Department of Anatomy and Neurobiology, Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Gyeongnam, South Korea.
Jae Yoon
JY
Han
Eun Young
EY
Jeong
Yoon Sook
YS
Kim
Gu Seob
GS
Roh
Hyun Joon
HJ
Kim
Sang Soo
SS
Kang
Gyeong Jae
GJ
Cho
Wan Sung
WS
Choi
D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000633:toxicity*; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051025:bcl-Associated Death Protein / Q000378:metabolism*
D048948:14-3-3 Proteins; C494821:Bad protein, rat; D002492:Central Nervous System Depressants; D051025:bcl-Associated Death Protein; D000431:Ethanol; D048031:JNK Mitogen-Activated Protein Kinases