Journal article
Bile Acid Regulation of C/EBPβ, CREB, and c-Jun Function, via the Extracellular Signal-Regulated Kinase and c-Jun NH2-Terminal Kinase Pathways, Modulates the Apoptotic Response of Hepatocytes
Molecular and cellular biology, Vol.23(9), pp.3052-3066
05/01/2003
DOI: 10.1128/MCB.23.9.3052-3066.2003
PMCID: PMC153195
PMID: 12697808
Abstract
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/EBPβ, CREB, and c-Jun/AP-1. Inhibition of C/EBPβ, 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/EBPβ, by inhibition of MEK1/2. The combined loss of CREB and c-Jun function or of C/EBPβ 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.
Details
- Title: Subtitle
- Bile Acid Regulation of C/EBPβ, CREB, and c-Jun Function, via the Extracellular Signal-Regulated Kinase and c-Jun NH2-Terminal Kinase Pathways, Modulates the Apoptotic Response of Hepatocytes
- Creators
- Liang Qiao - Virginia Commonwealth UniversitySong Iy Han - Departments of Radiation OncologyYouwen Fang - Departments of Radiation OncologyJong Sung Park - Departments of Radiation OncologySeema Gupta - University of IowaDonna Gilfor - Departments of Radiation OncologyGeorge Amorino - Departments of Radiation OncologyKristoffer Valerie - Departments of Radiation OncologyLinda Sealy - Vanderbilt UniversityJohn F. Engelhardt - University of IowaSteven Grant - Virginia Commonwealth UniversityPhilip B. Hylemon - Microbiology and ImmunologyPaul Dent - Departments of Radiation Oncology
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.23(9), pp.3052-3066
- Publisher
- American Society for Microbiology
- DOI
- 10.1128/MCB.23.9.3052-3066.2003
- PMID
- 12697808
- PMCID
- PMC153195
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Language
- English
- Date published
- 05/01/2003
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984284345402771
Metrics
9 Record Views