Regulation of ploidy and senescence by the AMPK‐related kinase NUAK1 |
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Authors: | Arnaud Augert Marco Da Costa Sébastien Martien Jing Wang Dolores Martinez Corinne Abbadie David Carling Yvan de Launoit Jesus Gil David Bernard |
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Institution: | 1. UMR8161, Institut de Biologie de Lille, CNRS/Universités de Lille 1 et 2/Institut Pasteur de Lille, Lille, France;2. UMR5238, Apoptose, Cancer et Développement, CNRS/Université de Lyon/Centre Léon Bérard, Lyon, France;3. Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK;4. University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Nebraska Medical Center, Omaha, NE, USA;5. London Research Institute, Cancer Research UK, London, UK;6. Cellular Stress Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK |
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Abstract: | Senescence is an irreversible cell‐cycle arrest that is elicited by a wide range of factors, including replicative exhaustion. Emerging evidences suggest that cellular senescence contributes to ageing and acts as a tumour suppressor mechanism. To identify novel genes regulating senescence, we performed a loss‐of‐function screen on normal human diploid fibroblasts. We show that downregulation of the AMPK‐related protein kinase 5 (ARK5 or NUAK1) results in extension of the cellular replicative lifespan. Interestingly, the levels of NUAK1 are upregulated during senescence whereas its ectopic expression triggers a premature senescence. Cells that constitutively express NUAK1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator LATS1, whereas depletion of NUAK1 with shRNA exerts opposite effects. Interestingly, a dominant‐negative form of LATS1 phenocopies NUAK1 effects. Moreover, we show that NUAK1 phosphorylates LATS1 at S464 and this has a role in controlling its stability. In summary, our work highlights a novel role for NUAK1 in the control of cellular senescence and cellular ploidy. |
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Keywords: | LATS1 NUAK1 senescence |
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