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

Nicolás Herranz, Suchira Gallage, Massimiliano Mellone, Torsten Wuestefeld, Sabrina Klotz, Christopher J Hanley, Selina Raguz, Juan Carlos Acosta, Andrew J Innes, Ana Banito, Athena Georgilis, Alex Montoya, Katharina Wolter, Gopuraja Dharmalingam, Peter Faull, Thomas Carroll, Juan Pedro Martínez-Barbera, Pedro Cutillas, Florian Reisinger, Mathias Heikenwalder, Richard A Miller, Dominic Withers, Lars Zender, Gareth J Thomas, Jesús Gil

Index: Nat. Cell Biol. 17 , 1205-17, (2015)

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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.