Journal
NATURE CELL BIOLOGY
Volume 17, Issue 9, Pages 1205-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3225
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Funding
- NIH [U01-AG022303]
- MRC
- EMBO fellowship
- BBSRC [BB/H020527/2] Funding Source: UKRI
- MRC [MC_U120085810, MR/M000125/1, MC_U120097114] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H020527/2] Funding Source: researchfish
- Cancer Research UK [13315, 16243] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [W1055] Funding Source: researchfish
- Medical Research Council [MR/M000125/1, MC_U120085810, 1375544, 1229061, MC_U120097114] Funding Source: researchfish
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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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