David E. Smart and Karen Green contributed equally to this work.
Liver Biology and Pathobiology
JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation†
Article first published online: 28 NOV 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 44, Issue 6, pages 1432–1440, December 2006
How to Cite
Smart, D. E., Green, K., Oakley, F., Weitzman, J. B., Yaniv, M., Reynolds, G., Mann, J., Millward-Sadler, H. and Mann, D. A. (2006), JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation. Hepatology, 44: 1432–1440. doi: 10.1002/hep.21436
Potential conflict of interest: Nothing to report.
- Issue published online: 28 NOV 2006
- Article first published online: 28 NOV 2006
- Manuscript Accepted: 7 SEP 2006
- Manuscript Received: 21 FEB 2006
- Wellcome Trust. Grant Numbers: 050443/Z, 068524/Z/02/Z
JunD is implicated in the regulation of hepatic stellate cell (HSC) activation and liver fibrosis via its transcriptional regulation of the tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. In the present study we found in vivo evidence of a role for JunD in fibrogenesis. Expression of JunD was demonstrated in alpha-SMA-positive activated HSCs of fibrotic rodents and human livers. The junD−/− mice were protected from carbon tetrachloride–induced fibrosis. The livers of injured junD−/− mice displayed significantly reduced formation of fibrotic crosslinked collagen and a smaller number of alpha-SMA-positive HSCs compared with those of wild-type (wt) mice. Hepatic TIMP-1 mRNA expression in injured junD−/− mice was 78% lower and in culture activated junD−/− HSCs was 50%-80% lower than that in wt mice. In examining the signal transduction mechanisms that regulate JunD-dependent TIMP-1 expression, we found a role for phosphorylation of the Ser100 residue of JunD but ruled out JNK as a mediator of this event, suggesting ERK1/2 is utilized. In conclusion, a signaling pathway for the development of fibrosis involves the regulation of TIMP-1 expression by phosphorylated JunD. (HEPATOLOGY 2006;44:1432–1440.)