JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation

Hepatology. 2006 Dec;44(6):1432-40. doi: 10.1002/hep.21436.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / immunology
  • Alanine Transaminase / metabolism
  • Animals
  • Anthracenes / pharmacology
  • Carbon Tetrachloride Poisoning / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibrinogen / biosynthesis
  • Flavonoids / pharmacology
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver / cytology
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / prevention & control
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / deficiency
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Rats
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects


  • Actins
  • Anthracenes
  • Flavonoids
  • Proto-Oncogene Proteins c-jun
  • Tissue Inhibitor of Metalloproteinase-1
  • Transcription Factors
  • smooth muscle actin, rat
  • pyrazolanthrone
  • Fibrinogen
  • Alanine Transaminase
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one