Co-Authors:
Gnainsky, Y., Institute of Animal Sciences, Volcani Center, P.O. Box 6, 50250 Bet Dagan, Israel
Spira, G., Department of Anatomy and Cell Biology, Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa, Israel
Paizi, M., Department of Anatomy and Cell Biology, Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa, Israel
Bruck, R., Department of Gastroenterology, E. Wolfson Medical Center, Holon, Israel
Nagler, A., Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel
Genina, O., Institute of Animal Sciences, Volcani Center, P.O. Box 6, 50250 Bet Dagan, Israel
Taub, R., Hoffmann-La Roche, Nutley, NJ, United States
Halevy, O., Department of Animal Sciences, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot, Israel
Pines, M., Institute of Animal Sciences, Volcani Center, P.O. Box 6, 50250 Bet Dagan, Israel
Abstract:
Tyrosine phosphatase PRL-1 is one of the immediate-early genes up-regulated during liver regeneration and is apparently involved in cell proliferation. Previously, we have demonstrated that halofuginone, an inhibitor of collagen type I synthesis, prevents liver fibrosis and improves cirrhotic liver regeneration. In this study, we evaluated the effect of halofuginone on PRL-1 expression, its cellular localization in vitro and during liver regeneration, and fibrosis progression in vivo. In culture, halofuginone increased PRL-1 expression in primary rat hepatocytes and in hepatocellular carcinoma (HCC) cell lines, the former being more sensitive to halofuginone. The halofuginone-dependent increase in PRL-1 gene expression was correlated with an increase in the transcription factor early growth response-1 (Egr-1) and inversely correlated with the inhibition of cell proliferation. Halofuginone arrested HepG2 and Huh7 cell lines at the G1 phase, whereas Hep3B cells were arrested at G2/M, probably because of a reduction in the synthesis of cyclins D1 and B1 in all HCC cells and increased cyclin A in Hep3B cells. Halofuginone also affected the PRL-1 subcellular localization that was cell-cycle-dependent. In addition, halofuginone augmented PRL-1 expression in the remnant liver after partial hepatectomy and in chemically induced fibrosis in rats; this was accompanied by increased expression of insulin-like growth factor binding protein 1 (IGFBP-1), another immediate-early gene of regeneration. The regulation of the expression of the early genes of regeneration such as PRL-1 and IGFBP-1 is thus part of the mode of action of halofuginone and results in the prevention of liver fibrosis and improved cirrhotic liver regeneration. © Springer-Verlag 2006.
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