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Distinct functions of JNK and c‐Jun in oxidant‐induced hepatocyte death
Author(s) -
Amir Muhammad,
Liu Kun,
Zhao Enpeng,
Czaja Mark J.
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.24203
Subject(s) - menadione , c jun , programmed cell death , hepatocyte , microbiology and biotechnology , apoptosis , oxidative stress , kinase , chemistry , phosphorylation , biology , biochemistry , transcription factor , in vitro , gene
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 β‐oxidation induced by menadione. This effect mediated cell death as chemical inhibition of β‐oxidation also sensitized cells to death from menadione, and supplementation with the β‐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: 3254–3265, 2012. © 2012 Wiley Periodicals, Inc.