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Molecular and Cellular Biology, May 2003, p. 3052-3066, Vol. 23, No. 9
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.9.3052-3066.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Bile Acid Regulation of C/EBPß, CREB, and c-Jun Function, via the Extracellular Signal-Regulated Kinase and c-Jun NH2-Terminal Kinase Pathways, Modulates the Apoptotic Response of Hepatocytes

Liang Qiao,1 Song Iy Han,1 Youwen Fang,1 Jong Sung Park,1 Seema Gupta,2 Donna Gilfor,1 George Amorino,1 Kristoffer Valerie,1 Linda Sealy,3 John F. Engelhardt,4 Steven Grant,5 Philip B. Hylemon,2 and Paul Dent1*

Departments of Radiation Oncology,1 Microbiology and Immunology,2 Hematology and Oncology, Virginia Commonwealth University, Richmond, Virginia 23298,5 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242,4 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 372323

Received 19 September 2002/ Returned for modification 25 October 2002/ Accepted 10 January 2003

Previously, we have demonstrated that deoxycholic acid (DCA)-induced signaling of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in primary hepatocytes is a protective response. In the present study, we examined the roles of the ERK and c-Jun NH2-terminal kinase (JNK) pathways, and downstream transcription factors, in the survival response of hepatocytes. DCA caused activation of the ERK1/2 and JNK1/2 pathways. Inhibition of either DCA-induced ERK1/2 or DCA-induced JNK1/2 signaling enhanced the apoptotic response of hepatocytes. Further analyses demonstrated that DCA-induced JNK2 signaling was cytoprotective whereas DCA-induced JNK1 signaling was cytotoxic. DCA-induced ERK1/2 activation was responsible for increased DNA binding of C/EBPß, CREB, and c-Jun/AP-1. Inhibition of C/EBPß, CREB, and c-Jun function promoted apoptosis following DCA treatment, and the level of apoptosis was further increased in the case of CREB and c-Jun, but not C/EBPß, by inhibition of MEK1/2. The combined loss of CREB and c-Jun function or of C/EBPß and c-Jun function enhanced DCA-induced apoptosis above the levels resulting from the loss of either factor individually; however, these effects were less than additive. Loss of c-Jun or CREB function correlated with increased expression of FAS death receptor and PUMA and decreased expression of c-FLIP-L and c-FLIP-S, proteins previously implicated in the modulation of the cellular apoptotic response. Collectively, these data demonstrate that multiple DCA-induced signaling pathways and transcription factors control hepatocyte survival.

* Corresponding author. Mailing address: Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, 401 College St., Richmond, VA 23298-0058. Phone: (804) 628-0861. Fax: (804) 828-6042. E-mail: pdent{at}hsc.vcu.edu.

Molecular and Cellular Biology, May 2003, p. 3052-3066, Vol. 23, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.9.3052-3066.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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