Regulation of ploidy and senescence by the AMPK-related kinase NUAK1.
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.
Humbert
Nicolas
N
UMR8161, Institut de Biologie de Lille, CNRS/Universités de Lille 1 et 2/Institut Pasteur de Lille, Lille, France.
Navaratnam
Naveenan
N
Augert
Arnaud
A
Da Costa
Marco
M
Martien
Sébastien
S
Wang
Jing
J
Martinez
Dolores
D
Abbadie
Corinne
C
Carling
David
D
de Launoit
Yvan
Y
Gil
Jesus
J
Bernard
David
D
D000091162:AMP-Activated Protein Kinase Kinases; D002460:Cell Line; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D010766:Phosphorylation; D011003:Ploidies; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D012097:Repressor Proteins; D011494:Protein Kinases; C092745:LATS1 protein, human; C470845:NUAK1 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases