JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation.
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.
Smart
David E
DE
Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK.
Green
Karen
K
Oakley
Fiona
F
Weitzman
Jonathan B
JB
Yaniv
Moshe
M
Reynolds
Gary
G
Mann
Jelena
J
Millward-Sadler
Harry
H
Mann
Derek A
DA
D000199:Actins / Q000276:immunology; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005340:Fibrinogen / Q000096:biosynthesis; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000517:prevention & control; D051379:Mice; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D000199:Actins; D000410:Alanine Transaminase; D000873:Anthracenes; D048049:Extracellular Signal-Regulated MAP Kinases; D005340:Fibrinogen; D005419:Flavonoids; D048031:JNK Mitogen-Activated Protein Kinases; D016755:Proto-Oncogene Proteins c-jun; D019715:Tissue Inhibitor of Metalloproteinase-1; D014157:Transcription Factors; C498862:Acta2 protein, rat; C432165:pyrazolanthrone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one