Published in
Nature Research, Nature Cell Biology, 10(17), p. 1370-1370, 2015
DOI: 10.1038/ncb3243
Nature Research, Nature Cell Biology, 9(17), p. 1205-1217, 2015
DOI: 10.1038/ncb3225
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- Nature Research | PDF
- Nature Research | PDF
- [eprints.soton.ac.uk]
- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [www.pure.ed.ac.uk] | PDF
- [www.research.ed.ac.uk] | PDF
- [europepmc.org] | PDF
- [discovery.ucl.ac.uk] | PDF
- [spiral.imperial.ac.uk] | PDF
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mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
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Abstract
Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.