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.
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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 > School of Life and Medical 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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