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Nat Cell Biol. 2015 Sep;17(9):1205-17. doi: 10.1038/ncb3225. Epub 2015 Aug 17.

mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.

Author information

1
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
2
Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
3
Metabolic Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
4
Cancer Sciences Unit, Cancer Research UK Centre, Somers Building, University of Southampton, Southampton SO16 6YD, UK.
5
Division of Molecular Oncology of Solid Tumors, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
6
Proteomics Facility, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
7
Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK.
8
Institute for Virology, Technische Universität München/Helmholtz Zentrum München, 81675 Munich, Germany.
9
Division of Chronic Inflammation and Cancer, German Cancer Research (DKFZ), 69121 Heidelberg, Germany.
10
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.

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.

Comment in

PMID:
26280535
PMCID:
PMC4589897
DOI:
10.1038/ncb3225
[Indexed for MEDLINE]
Free PMC Article

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