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

Herranz, N; Gallage, S; Mellone, M; Wuestefeld, T; Klotz, S; Hanley, CJ; Raguz, S; ... Gil, J; + view all (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nature Cell Biology , 17 (9) pp. 1205-1217. 10.1038/ncb3225. Green open access

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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.

Type: Article
Title: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ncb3225
Publisher version: http://dx.doi.org/10.1038/ncb3225
Language: English
Keywords: mTOR, SASP, senescence, rapamycin, MAPKAPK2, ZFP36L1.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1470188
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