Journal
EMBO JOURNAL
Volume 29, Issue 2, Pages 376-386Publisher
WILEY
DOI: 10.1038/emboj.2009.342
Keywords
LATS1; NUAK1; senescence
Categories
Funding
- Association pour la Recherche sur le Cancer
- Fondation pour la Recherche Medicale Nord Pas de Calais
- Comite du Pas de Calais de la Ligue Nationale contre le Cancer
- RTRS Fondation Synergie Lyon Cancer
- Medical Research Council, UK
- Medical Research Council [MC_U120085810, MC_U120027537] Funding Source: researchfish
- MRC [MC_U120085810, MC_U120027537] Funding Source: UKRI
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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. The EMBO Journal (2010) 29, 376-386. doi: 10.1038/emboj.2009.342; Published online 19 November 2009
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