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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

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.

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