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

Nicolas Humbert, Naveenan Navaratnam, 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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58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)376-386
Number of pages11
JournalEMBO Journal
Volume29
Issue number2
DOIs
StatePublished - Jan 1 2010

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Keywords

  • LATS1
  • NUAK1
  • Senescence

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Humbert, N., Navaratnam, N., Augert, A., Da Costa, M., Martien, S., Wang, J., Martinez, D., Abbadie, C., Carling, D., De Launoit, Y., Gil, J., & Bernard, D. (2010). Regulation of ploidy and senescence by the AMPK-related kinase NUAK1. EMBO Journal, 29(2), 376-386. https://doi.org/10.1038/emboj.2009.342