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EMBO J. 2010 Jan 20;29(2):376-86. doi: 10.1038/emboj.2009.342. Epub 2009 Nov 19.

Regulation of ploidy and senescence by the AMPK-related kinase NUAK1.

Author information

1
UMR8161, Institut de Biologie de Lille, CNRS/Universités de Lille 1 et 2/Institut Pasteur de Lille, Lille, France.

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.

PMID:
19927127
PMCID:
PMC2824453
DOI:
10.1038/emboj.2009.342
[Indexed for MEDLINE]
Free PMC Article
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