JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation.
Hepatology
; 44(6): 1432-40, 2006 Dec.
Article
em En
| MEDLINE
| ID: mdl-17133482
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Proteínas Proto-Oncogênicas c-jun
/
Cirrose Hepática
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article