Cell and Tissue Research

, Volume 324, Issue 3, pp 385–394 | Cite as

Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL–1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone

  • Yulia   Gnainsky
  • Gadi   Spira
  • Melia   Paizi
  • Raffael   Bruck
  • Arnon   Nagler
  • Olga   Genina
  • Rebbeca   Taub
  • Orna   Halevy
  • Mark   Pines
Regular Article

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 sub-cellular 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.

Keywords

Fibrosis   Egr–1   p53   PRL–2   Collagen   Human   Rat  

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Yulia   Gnainsky
    • 1
  • Gadi   Spira
    • 2
  • Melia   Paizi
    • 2
  • Raffael   Bruck
    • 3
  • Arnon   Nagler
    • 4
  • Olga   Genina
    • 1
  • Rebbeca   Taub
    • 5
  • Orna   Halevy
    • 6
  • Mark   Pines
    • 1
  1. 1. Institute of Animal sciences Volcani Center Bet Dagan Israel
  2. 2. Department of Anatomy and Cell Biology, Bruce Rappaport, Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences Technion Haifa Israel
  3. 3. Department of Gastroenterology E. Wolfson Medical Center Holon Israel
  4. 4. Department of Hematology and Bone Marrow Transplantation Chaim Sheba Medical Center Tel Hashomer Israel
  5. 5. Hoffmann–La Roche Nutley USA
  6. 6. Department of Animal Sciences, Faculty of Agriculture The Hebrew University of Jerusalem Rehovot Israel

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