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oai:repisalud.isciii.es:20.500.12105/174122024-11-29T23:02:58Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Humbert, Nicolas author Navaratnam, Naveenan author Augert, Arnaud author Da Costa, Marco author Martien, Sébastien author Wang, Jing author Martinez Garcia, Maria Dolores author Abbadie, Corinne author Carling, David author de Launoit, Yvan author Gil, Jesús author Bernard, David author 2010-01-20 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. EMBO J . 2010 ;29(2):376-86. 10.1038/emboj.2009.342 1460-2075 The EMBO journal 19927127 http://hdl.handle.net/20.500.12105/17412 Regulation of ploidy and senescence by the AMPK-related kinase NUAK1.