Herranz, Nicolás, Gallage, Suchira, Mellone, Massimiliano, Wuestefeld, Torsten, Klotz, Sabrina, Hanley, Christopher J., Raguz, Selina, Acosta, Juan Carlos, Innes, Andrew J., Banito, Ana, Georgilis, Athena, Montoya, Alex, Wolter, Katharina, Dharmalingam, Gopuraja, Faull, Peter, Carroll, Thomas, Martínez-Barbera, Juan Pedro, Cutillas, Pedro, Reisinger, Florian, Heikenwalder, Mathias, Miller, Richard A., Withers, Dominic, Zender, Lars, Thomas, Gareth J. and Gil, Jesús (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nature Cell Biology, 17 (9), 1205-1217. (doi:10.1038/ncb3225). (PMID:26280535)
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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