Glutathione transferases P1/P2 regulate the timing of signaling pathway activations and cell cycle progression during mouse liver regeneration

J. Pajaud, C. Ribault, I. Ben Mosbah, C. Rauch, C. Henderson, P. Bellaud, C. Aninat, P. Loyer, F. Morel, A. Corlu (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    11 Citations (Scopus)

    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.

    Original languageEnglish
    Article numbere1598
    Number of pages13
    JournalCell Death and Disease
    Volume6
    DOIs
    Publication statusPublished - 15 Jan 2015

    Fingerprint

    Liver Regeneration
    Glutathione Transferase
    Hepatocytes
    Cell Cycle
    Hepatectomy
    MAP Kinase Signaling System
    Knockout Mice
    Enzyme Induction
    Mitotic Index
    Wild Animals
    Liver
    Cyclin D1
    G1 Phase
    Xenobiotics
    DNA Replication
    Nitric Oxide Synthase
    Interleukin-6
    Tumor Necrosis Factor-alpha
    Antioxidants
    Phosphorylation

    Cite this

    Pajaud, J. ; Ribault, C. ; Ben Mosbah, I. ; Rauch, C. ; Henderson, C. ; Bellaud, P. ; Aninat, C. ; Loyer, P. ; Morel, F. ; Corlu, A. / Glutathione transferases P1/P2 regulate the timing of signaling pathway activations and cell cycle progression during mouse liver regeneration. In: Cell Death and Disease. 2015 ; Vol. 6.
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    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.",
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    Glutathione transferases P1/P2 regulate the timing of signaling pathway activations and cell cycle progression during mouse liver regeneration. / Pajaud, J.; Ribault, C.; Ben Mosbah, I.; Rauch, C.; Henderson, C.; Bellaud, P.; Aninat, C.; Loyer, P.; Morel, F.; Corlu, A. (Lead / Corresponding author).

    In: Cell Death and Disease, Vol. 6, e1598, 15.01.2015.

    Research output: Contribution to journalArticle

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    AU - Ribault, C.

    AU - Ben Mosbah, I.

    AU - Rauch, C.

    AU - Henderson, C.

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    AU - Aninat, C.

    AU - Loyer, P.

    AU - Morel, F.

    AU - Corlu, A.

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