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Journal of Biochemistry Advance Access originally published online on March 20, 2009
Journal of Biochemistry 2009 146(1):123-132; doi:10.1093/jb/mvp052
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© The Authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

Gene Expression Profiling Identifies a Role for CHOP During Inhibition of the Mitochondrial Respiratory Chain

Fumihiro Ishikawa1, Takashi Akimoto1, Haruka Yamamoto1, Yuri Araki1, Toshihiko Yoshie1, Kazunori Mori1, Hidetoshi Hayashi2, Kiyoshi Nose1 and Motoko Shibanuma1,*

1Department of Microbiology, Showa University School of Pharmacy, Tokyo 142-8555; and 2Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-cho, Nagoya, Aichi, Japan

*To whom correspondence should be addressed: Tel: +81-3-3784-8209, Fax: +81-3-3784-6850, E-mail: smotoko{at}pharm.showa-u.ac.jp

Received December 29, 2008; Accepted March 7, 2009


  Abstract

Mitochondrial dysfunction, in particular, interference in the respiratory chain, is often responsible for the toxicogenic effects of xenobiotics. In this study, changes in gene expression resulting from pharmacological inhibition of the respiratory chain were studied by DNA microarray analysis using cells treated with rotenone or antimycin A, which inhibit complexes I and III of the electron transport system, respectively. Forty-eight genes were either up- or down-regulated more than 3-fold. These included stress- and/or metabolic-related effector genes and several transcriptional regulators represented by CHOP-10. Further study using siRNA showed that among the four genes studied, up-regulation of three was dependent on CHOP-10. C/EBPβ, a dimerizing partner of CHOP-10, was also involved in two of the three genes including Trib3, implying that CHOP-10, heterodimerizing with C/EBPβ or another partner played a key role in the expression of a set of genes under stress. Although CHOP-10 and Trib3 were both ER-stress response genes, signal inducing Trib3 during mitochondrial stress was distinct from that during ER stress. Cytotoxicity caused by inhibition of the respiratory chain was attenuated by treatment with siRNA for CHOP-10. This study demonstrated the importance of CHOP-10 in coordinating individual gene expression in response to the mitochondrial stress.

Key Words: C/EBPβ, CHOP-10, DNA microarray, mitochondrial stress, respiratory chain

Abbreviations: CHOP, CCAAT/enhancer-binding protein (C/EBP) homology protein-10; C/EBP, CCAAT/enhancer-binding protein; ER, endoplasmic reticulum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RT–PCR, reverse transcription-polymerase chain reaction; Trib3, tribbles-related protein 3


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