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Dual regulation of hepatocyte apoptosis by reactive oxygen species: Increases in transcriptional expression and decreases in proteasomal degradation of BimEL
Author(s) -
Ishihara Yasuhiro,
Takeuchi Kenji,
Ito Fumiaki,
Shimamoto Norio
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22414
Subject(s) - reactive oxygen species , microbiology and biotechnology , apoptosis , hepatocyte , mapk/erk pathway , signal transduction , biology , intracellular , extracellular , phosphorylation , kinase , programmed cell death , biochemistry , in vitro
Reactive oxygen species (ROS) have a fundamental role in intracellular signaling transduction. We show here that time‐dependent extracellular signal‐regulated kinase (ERK) activation due to inactivation of protein tyrosine phosphatases was closely linked to hepatocyte apoptosis under sustained exposure to ROS, which is produced through inhibition of ROS‐scavenging enzymes. We found, for the first time, that active ERK transcriptionally increased BimEL expression among seven proteins of the Bcl‐2 family. Transfection of Bim siRNA inhibited BimEL expression and hepatocyte apoptosis. Although ERK activation also elicited BimEL phosphorylation and subsequent ubiquitination, exposure to ROS for 9 h decreased proteasome activity. Collectively, the amount of BimEL was elevated by its increased expression and decreased degradation, leading to apoptosis. Exposure to ROS for 6 h caused neither reduction of proteasome activity nor hepatocyte apoptosis. These results indicate that the duration of exposure to ROS determines the fate of cells, that is, survival or death, in addition to the species, amounts, and generation sites of ROS. J. Cell. Physiol. 226: 1007–1016, 2011. © 2010 Wiley‐Liss, Inc.