Glutathione transferases P1/P2 regulate the timing of signaling pathway activations and cell cycle progression during mouse liver regeneration
| Autor: | Pascale Bellaud, I. Ben Mosbah, Colin J. Henderson, Pascal Loyer, Caroline Aninat, Frédéric Morel, Anne Corlu, Julie Pajaud, Catherine Ribault, Claudine Rauch |
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| Přispěvatelé: | Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme d'histopathologie, Université de Rennes (UR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Time Factors Cell Survival Liver cytology [SDV]Life Sciences [q-bio] Immunology Biology 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Stress Physiological medicine Animals Hepatectomy RNA Messenger Extracellular Signal-Regulated MAP Kinases Cell Proliferation Glutathione Transferase 030304 developmental biology 0303 health sciences Cell Death Cell growth Gene Expression Profiling Cell Cycle JNK Mitogen-Activated Protein Kinases Cell Biology Cell cycle Liver regeneration Liver Regeneration Cell biology Mice Inbred C57BL Protein Transport medicine.anatomical_structure Gene Expression Regulation Glutathione S-Transferase pi Liver 030220 oncology & carcinogenesis Hepatocyte Knockout mouse Hepatocytes Phosphorylation Original Article Signal transduction Signal Transduction |
| Zdroj: | Cell Death and Disease Cell Death and Disease, 2015, 6 (1), pp.e1598. ⟨10.1038/cddis.2014.562⟩ Cell Death & Disease Cell Death and Disease, Nature Publishing Group, 2015, 6 (1), pp.e1598. ⟨10.1038/cddis.2014.562⟩ |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/cddis.2014.562⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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