• An Erratum to this article was published on 30 September 2015

This article has been updated

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.

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Change history

  • 28 August 2015

    In the original version of this Article, a sentence was changed in error during production. This sentence should have read ‘To understand to what extent mTOR regulates the SASP, we analysed the secretome of senescent cells by mass spectrometry (MS; refs 24, 25).’ There was a further typographical error in one instance of ‘SASP components’. These errors have been corrected in all online versions of the Article.

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Acknowledgements

We are grateful to T. Rodríguez, A. Nebreda, R. Agami, M. Gaestel, D. Engelberg, G. Wendel, J. Campisi, C. Moroni, C. Speck, A. Day and G. Peters for reagents, helpful comments and contributions to this project. R. Miller is funded by NIH Grant U01-AG022303. Core support from MRC funded the research in J. Gil’s laboratory. N. Herranz was funded by an EMBO fellowship.

Author information

Author notes

    • Torsten Wuestefeld
    •  & Pedro Cutillas

    Present addresses: Stem Cell & Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore (T.W.); Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK (P.C.).

Affiliations

  1. Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK

    • Nicolás Herranz
    • , Suchira Gallage
    • , Selina Raguz
    • , Juan Carlos Acosta
    • , Andrew J. Innes
    • , Ana Banito
    • , Athena Georgilis
    •  & Jesús Gil
  2. Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK

    • Nicolás Herranz
    • , Suchira Gallage
    • , Selina Raguz
    • , Juan Carlos Acosta
    • , Andrew J. Innes
    • , Ana Banito
    • , Athena Georgilis
    • , Gopuraja Dharmalingam
    • , Thomas Carroll
    •  & Jesús Gil
  3. Metabolic Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK

    • Suchira Gallage
    •  & Dominic Withers
  4. Cancer Sciences Unit, Cancer Research UK Centre, Somers Building, University of Southampton, Southampton SO16 6YD, UK

    • Massimiliano Mellone
    • , Christopher J. Hanley
    •  & Gareth J. Thomas
  5. Division of Molecular Oncology of Solid Tumors, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany

    • Torsten Wuestefeld
    • , Sabrina Klotz
    • , Katharina Wolter
    •  & Lars Zender
  6. Proteomics Facility, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK

    • Alex Montoya
    • , Peter Faull
    •  & Pedro Cutillas
  7. Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK

    • Juan Pedro Martínez-Barbera
  8. Institute for Virology, Technische Universität München/Helmholtz Zentrum München, 81675 Munich, Germany

    • Florian Reisinger
    •  & Mathias Heikenwalder
  9. Division of Chronic Inflammation and Cancer, German Cancer Research (DKFZ), 69121 Heidelberg, Germany

    • Mathias Heikenwalder
  10. Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109-2200, USA

    • Richard A. Miller

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Contributions

N.H. and J.G. designed the experiments. N.H., S.G., M.M., C.J.H., S.R., J.C.A., A.J.I., A.B. and A.G. carried out and analysed the cell culture experiments. N.H., S.G., M.M., T.W., S.K., K.W., C.J.H. and F.R. carried out and analysed the animal experiments. N.H., S.G. and J.G. wrote the paper. P.F. and A.M. carried out the mass spectrometry experiments and analysis, supervised by P.C. G.D. and T.C. carried out the bioinformatics analysis. R.M. provided mouse samples and J.P.M.-B. provided reagents. All authors interpreted data, discussed results and revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jesús Gil.

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DOI

https://doi.org/10.1038/ncb3225

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