期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 113, 期 10, 页码 3254-3265出版社
WILEY-BLACKWELL
DOI: 10.1002/jcb.24203
关键词
APOPTOSIS; ATP; FATTY ACID OXIDATION; MENADIONE; NECROSIS
资金
- National Institutes of Health [DK044234, DK007218]
Overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling is a central mechanism of hepatocyte injury and death including that from oxidative stress. However, the functions of JNK and c-Jun are still unclear, and this pathway also inhibits hepatocyte death. Previous studies of menadione-induced oxidant stress demonstrated that toxicity resulted from sustained JNK/c-Jun activation as death was blocked by the c-Jun dominant negative TAM67. To further delineate the function of JNK/c-Jun signaling in hepatocyte injury from oxidant stress, the effects of direct JNK inhibition on menadione-induced death were examined. In contrast to the inhibitory effect of TAM67, pharmacological JNK inhibition by SP600125 sensitized the rat hepatocyte cell line RALA255-10G to death from menadione. SP600125 similarly sensitized mouse primary hepatocytes to menadione toxicity. Death from SP600125/menadione was c-Jun dependent as it was blocked by TAM67, but independent of c-Jun phosphorylation. Death occurred by apoptosis and necrosis and activation of the mitochondrial death pathway. Short hairpin RNA knockdowns of total JNK or JNK2 sensitized to death from menadione, whereas a jnk1 knockdown was protective. Jnk2 null mouse primary hepatocytes were also sensitized to menadione death. JNK inhibition magnified decreases in cellular ATP content and beta-oxidation induced by menadione. This effect mediated cell death as chemical inhibition of beta-oxidation also sensitized cells to death from menadione, and supplementation with the beta-oxidation substrate oleate blocked death. Components of the JNK/c-Jun signaling pathway have opposing functions in hepatocyte oxidant stress with JNK2 mediating resistance to cell death and c-Jun promoting death. J. Cell. Biochem. 113: 32543265, 2012. (c) 2012 Wiley Periodicals, Inc.
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