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

Authors

  • David E. Smart,

    1. Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK
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    • David E. Smart and Karen Green contributed equally to this work.

  • Karen Green,

    1. Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK
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    • David E. Smart and Karen Green contributed equally to this work.

  • Fiona Oakley,

    1. Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK
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  • Jonathan B. Weitzman,

    1. Centre National de La Recherche Scientifique URA1644, Unit of Gene Expression & Disease, Department of Developmental Biology, Institut Pasteur, Paris, France
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  • Moshe Yaniv,

    1. Centre National de La Recherche Scientifique URA1644, Unit of Gene Expression & Disease, Department of Developmental Biology, Institut Pasteur, Paris, France
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  • Gary Reynolds,

    1. Liver Research Laboratories, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, UK
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  • Jelena Mann,

    1. Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK
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  • Harry Millward-Sadler,

    1. Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK
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  • Derek A. Mann

    Corresponding author
    1. Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK
    • Liver Research Group, Institute of Cellular Medicine, Level 4, Catherine Cookson Building, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE24HH, UK
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  • Potential conflict of interest: Nothing to report.

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. (HEPATOLOGY 2006;44:1432–1440.)

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