JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation
Open Access
- 28 November 2006
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 44 (6), 1432-1440
- https://doi.org/10.1002/hep.21436
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.)Keywords
This publication has 35 references indexed in Scilit:
- Regulation of Tissue Inhibitor of Metalloproteinase 1 Gene Transcription by RUNX1 and RUNX2Journal of Biological Chemistry, 2004
- Induction of myofibroblast MMP-9 transcription in three-dimensional collagen I gel cultures: regulation by NF-κB, AP-1 and Sp1The International Journal of Biochemistry & Cell Biology, 2003
- Inhibition of Apoptosis of Activated Hepatic Stellate Cells by Tissue Inhibitor of Metalloproteinase-1 Is Mediated via Effects on Matrix Metalloproteinase InhibitionPublished by Elsevier BV ,2002
- Extracellular Matrix Degradation and the Role of Hepatic Stellate CellsSeminars in Liver Disease, 2001
- JunD Regulates Transcription of the Tissue Inhibitor of Metalloproteinases-1 and Interleukin-6 Genes in Activated Hepatic Stellate CellsPublished by Elsevier BV ,2001
- Upstream Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Element-1, a Novel and Essential Regulatory DNA Motif in the Human TIMP-1 Gene Promoter, Directly Interacts with a 30-kDa Nuclear ProteinPublished by Elsevier BV ,2000
- Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue InjuryJournal of Biological Chemistry, 2000
- Control of the tissue inhibitor of metalloproteinases-1 promoter in culture-activated rat hepatic stellate cells: Regulation by activator protein-1 DNA binding proteinsHepatology, 1999
- Transcriptional activity of the human tissue inhibitor of metalloproteinases 1 (TIMP-1) gene in fibroblasts involves elements in the promoter, exon 1 and intron 1Biochemical Journal, 1997
- AP-1 function and regulationCurrent Opinion in Cell Biology, 1997