Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes.

Qiao L, Han SI, Fang Y, Park JS, Gupta S, Gilfor D, Amorino G, Valerie K, Sealy L, Engelhardt JF, Grant S, Hylemon PB, Dent P
Mol Cell Biol. 2003 23 (9): 3052-66

PMID: 12697808 · PMCID: PMC153195 · DOI:10.1128/mcb.23.9.3052-3066.2003

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 NH(2)-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/EBPbeta, CREB, and c-Jun/AP-1. Inhibition of C/EBPbeta, 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/EBPbeta, by inhibition of MEK1/2. The combined loss of CREB and c-Jun function or of C/EBPbeta 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.

MeSH Terms (26)

Amino Acid Sequence Animals Apoptosis Bile Acids and Salts Carrier Proteins CASP8 and FADD-Like Apoptosis Regulating Protein CCAAT-Enhancer-Binding Proteins Cells, Cultured Cell Survival Cyclic AMP Response Element-Binding Protein Deoxycholic Acid Enzyme Inhibitors fas Receptor Hepatocytes Intracellular Signaling Peptides and Proteins JNK Mitogen-Activated Protein Kinases Male Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinase 9 Mitogen-Activated Protein Kinases Molecular Sequence Data Rats Rats, Sprague-Dawley Signal Transduction Transcription Factor AP-1

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