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    LKB1: a master gatekeeper of hepatocyte renewal and genomic integrity

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    A study directed by Chantal Desdouets

    The liver is an organ with a fantastic ability to regenerate.

    Indeed, if part of the liver is injured or removed surgically, there is an increase of cell divisions such that the liver can restore very quickly its initial size. How to induce regeneration of hepatic tissue? Partial hepatectomy that defines a resection is a commonly indicated medical procedure. This operation is thus practiced in patients suffering from massive necrosis during viral or toxic hepatitis, hepatic tumors, benign or malignant hepatic malformations. At the end of the regeneration of the tissue, the organ recovers not only its starting weight but also its physiological functions (metabolic, detoxification ...) which are essential for survival. Understanding the mechanisms involved in hepatic regeneration is essential for the development of clinical strategies that improve regeneration efficiency. The study conducted by Chantal Desdouets' team, Inserm - Institut Cochin, published on 21 February 2018 in Cell Reports reveals the major role of LKB1 kinase (liver kinase B1) in liver regeneration.

    LKB1 protein is commonly called « master kinase ». Indeed, LKB1 is capable of regulating the activity of at least 14 different targets, thus controlling a wide range of biological processes. Originally discovered as a tumor suppressor gene, LKB1 is also mutated in various human cancers. In the adult liver, LKB1 plays a major role in the control of carbohydrate and lipid homeostasis. However, its involvement during liver regeneration process had never been characterized. By performing liver hepatectomy on LKB1-deficient mice, specifically in hepatocytes, the authors discovered two essential roles of LKB1 in liver regeneration. First, LKB1 controls hepatocyte proliferation by regulating the activity of the receptor binding the epidermal growth factor (EGFR). Indeed, LKB1 regulates EGFR phosphorylation, but also the expression of the gene coding this receptor. It is interesting to note that receptor activation is essential for the regenerative response, but EGFR pathway is also known to be dysregulated in liver cancer. Secondly, the authors demonstrate that LKB1 is a guardian of genomic integrity by controlling mitosis progression. During metaphase, LKB1 assures the organization and orientation of a normal microtubule spindle. This event is essential to the correct chromosomal segregation and allows for an equivalent distribution of genomic material during cell division. LKB1 thus allows to avoid the emergence of chromosomal instability, a well-known stigmata of transformation process.

    To conclude, these works demonstrate that LKB1 kinase is essential to maintain controlled liver regeneration. These results have a major implication in the clinical field since they reveal the importance to monitor that LKB1 kinase activity is not impaired in the liver of patient undergoing surgical resection. The measurement of hepatic LKB1 activity will allow to identify patients with a higher probability to recover physiological liver functions after hepatectomy.

     

     

     

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    Bibliography

    LKB1 as a Gatekeeper of Hepatocyte Proliferation and Genomic Integrity during Liver Regeneration.
    Vanessa Maillet, Nadia Boussetta, Jocelyne Leclerc, Véronique Fauveau, Marc Foretz, Benoit Viollet, Jean-Pierre Couty, Séverine Celton-Morizur, Christine Perret, Chantal Desdouets.
    Cell Reports 22, 1994–2005, February 20, 2018.

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    A scientific news has been written in collaboration with the CNRS and published on the INSB website: www.cnrs.fr