Protein tyrosine phosphatase of liver regeneration-1 is required for normal timing of cell cycle progression during liver regeneration.
Protein tyrosine phosphatase of liver regeneration-1 (Prl-1) is an immediate-early gene that is significantly induced during liver regeneration. Several in vitro studies have suggested that Prl-1 is important for the regulation of cell cycle progression. To evaluate its function in liver regeneration, we ablated the Prl-1 gene specifically in mouse hepatocytes using the Cre-loxP system. Prl-1 mutant mice (Prl-1(loxP/loxP);AlfpCre) appeared normal and fertile. Liver size and metabolic function in Prl-1 mutants were comparable to controls, indicating that Prl-1 is dispensable for liver development, postnatal growth, and hepatocyte differentiation. Mutant mice demonstrated a delay in DNA synthesis after 70% partial hepatectomy, although ultimate liver mass restoration was not affected. At 40 h posthepatectomy, reduced protein levels of the cell cycle regulators cyclin E, cyclin A2, cyclin B1, and cyclin-dependent kinase 1 were observed in Prl-1 mutant liver. Investigation of the major signaling pathways involved in liver regeneration demonstrated that phosphorylation of protein kinase B (AKT) and signal transducer and activator of transcription (STAT) 3 were significantly reduced at 40 h posthepatectomy in Prl-1 mutants. Taken together, this study provides evidence that Prl-1 is required for proper timing of liver regeneration after partial hepatectomy. Prl-1 promotes G1/S progression via modulating expression of several cell cycle regulators through activation of the AKT and STAT3 signaling pathway.
Department of Genetics and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania;
Yang
Y
Jiao
Department of Genetics and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania;
Diana Z
DZ
Ye
Department of Genetics and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania;
Zhaoyu
Z
Li
Department of Genetics and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania;
Monica
M
Teta-Bissett
Department of Genetics and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania;
Yong
Y
Peng
VIA Pharmaceuticals, Fort Washington, Pennsylvania.
Rebecca
R
Taub
Department of Cancer Biology, School of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Linda E
LE
Greenbaum
Department of Genetics and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania; kaestner@mail.med.upenn.edu.
Klaus H
KH
Kaestner
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
D017874:Immediate-Early Proteins; D017027:Protein Tyrosine Phosphatases; C087359:Ptp4a1 protein, mouse
hepatectomy; protein tyrosine phosphatase