Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL-1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone.
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.
Gnainsky
Yulia
Y
Institute of Animal sciences , Volcani Center , P.O. Box 6 , 50250 Bet Dagan , Israel.
Spira
Gadi
G
Paizi
Melia
M
Bruck
Raffael
R
Nagler
Arnon
A
Genina
Olga
O
Taub
Rebbeca
R
Halevy
Orna
O
Pines
Mark
M
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D052999:Quinazolinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D010880:Piperidines; D052999:Quinazolinones; D017027:Protein Tyrosine Phosphatases; C490199:Ptp4a1 protein, rat; C010176:halofuginone