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- Title
Regulation of ploidy and senescence by the AMPK-related kinase NUAK1.
- Authors
Humbert, Nicolas; Navaratnam, Naveenan; Augert, Arnaud; Da Costa, Marco; Martien, Sébastien; Jing Wang; Martinez, Dolores; Abbadie, Corinne; Carling, David; de Launoit, Yvan; Gil, Jesus; Bernard, David
- 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.
- Subjects
AGING; GENES; FIBROBLASTS; PROTEIN kinases; CELL cycle
- Publication
EMBO Journal, 2010, Vol 29, Issue 2, p376
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/emboj.2009.342