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Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death

Koh, SS; Park, EH; Cho, IR; Min, HJ; Jhun, BH; Yu, DY; Park, S; Park, do Y; Lee, MO; Castrillon, DH; Johnston, RN; Chung, YH
International journal of molecular medicine, 28(2):255-260, 2011
Journal Title
International journal of molecular medicine
The hepatitis B virus X (HBX) protein, a regulatory protein of the hepatitis B virus (HBV), has been shown to generate reactive oxygen species (ROS) in human liver cell lines; however, the mechanism by which cells protect themselves under this oxidative stress is poorly understood. Here, we show that HBX induces the up-regulation of Forkhead box class O 4 (Foxo4) not only in Chang cells stably expressing HBX (Chang-HBX) but also in primary hepatic tissues from HBX-transgenic mice. HBX also increased ROS, but reduction of the abundance of ROS using N-acetylcystein (NAC) diminished the levels of Foxo4. Elevated Foxo4 was also detected in nuclei of Chang-HBX cells but not in Chang cells stably expressing the vector (Chang-Vec), suggesting that HBX activates the transcriptional activity of Foxo4. When we examined whether HBX bypasses JNK signaling that targets Foxo4, we found that the activity of JNK but not of ERK is required for the up-regulation of Foxo4 even in the presence of HBX. Furthermore, the reduction of Foxo4 levels using siRNA or a JNK inhibitor rendered Chang-HBX cells sensitive to apoptosis under oxidative stress, suggesting that up-regulation of Foxo4 mediated by HBX enhances resistances to oxidative stress-induced cell death. Accordingly, we propose that Foxo4 may be a useful target for suppression in the treatment of HBV-associated hepatocellular carcinoma cells.
MeSH terms
AnimalsCell DeathCell LineCell Nucleus/metabolismForkhead Transcription Factors/antagonists & inhibitors/*genetics/*metabolismGene Expression RegulationHumansMAP Kinase Kinase 4/antagonists & inhibitorsMiceMice, Inbred C57BLMice, TransgenicOxidative Stress/*geneticsProtein Transport/geneticsReactive Oxygen Species/metabolismTrans-Activators/*genetics/*metabolism*Up-Regulation
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
AJOU Authors
박, 선
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