title: Glutathione transferases P1/P2 regulate the timing of signaling pathway activations and cell cycle progression during mouse liver regeneration.
abstract: Glutathione transferases (GST) are phase II enzymes catalyzing the detoxification of endogenous noxious compounds and xenobiotics. They also regulate phosphorylation activities of MAPKinases in a catalytic-independent manner. Previous studies have demonstrated the regulation of JNK-dependent pathway by GSTP1/2. Considering the crucial role of JNK in the early steps of the hepatocyte cell cycle, we sought to determine whether GSTP1/2 were essential for hepatocyte proliferation following partial hepatectomy (PH). Using a conventional double knockout mouse model for the Gstp1 and Gstp2 genes, we found that the lack of GSTP1/P2 reduced the rate of DNA replication and mitotic index during the first wave of hepatocyte proliferation. The lowered proliferation was associated with the decrease in TNFalpha and IL-6 plasma concentrations, reduced hepatic HGF expression and delayed and/or altered activation of STAT3, JNK and ERK1/2 signaling pathways. In addition, the expression and/or activation of cell cycle regulators such as Cyclin D1, CDK4, E2F1 and MCM7 was postponed demonstrating that the absence of GSTP1/2 delayed the entry into and progression through the G1 phase of the cell cycle and impaired the synchrony of proliferation in hepatocytes following PH. Furthermore, while JNK and its downstream targets c-Jun and ATF2 were activated during the early steps of the liver regeneration in wild-type animals, the constitutively active JNK found in the quiescent liver of Gstp1/2 knockout mice underwent a decrease in its activity after PH. Transient induction of antioxidant enzymes and nitric oxide synthase were also delayed or repressed during the regenerative response. Altogether our results demonstrate that GSTP1/2 are a critical regulators of hepatocyte proliferation in the initial phases of liver regeneration.
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: J
authors.initials: J
authors.lastname: Pajaud
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Ribault
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: I
authors.initials: I
authors.lastname: Ben Mosbah
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Rauch
authors.affiliation: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: C
authors.initials: C
authors.lastname: Henderson
authors.affiliation: 1] Université de Rennes 1, Faculté de Médecine, Rennes, France [2] Plateforme Histopathologie H2P2, Biosit, Biogenouest, Université de Rennes 1, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Bellaud
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Aninat
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Loyer
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: F
authors.initials: F
authors.lastname: Morel
authors.affiliation: 1] Inserm, UMR 991, Liver, Metabolisms and Cancer, CHU Pontchaillou, Rennes, France [2] Université de Rennes 1, Faculté de Médecine, Rennes, France.
authors.forename: A
authors.initials: A
authors.lastname: Corlu
mesh_terms: D000818:Animals; D002453:Cell Cycle; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D013997:Time Factors
chemical_list: C000601189:Gstp2 protein, mouse; D012333:RNA, Messenger; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases