학술논문
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
Document Type
Article
Author
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
Source
Subject
*OLD age
*GENOTYPE-environment interaction
*PHENOTYPES
*NEOPLASTIC cell transformation
*GENOTYPES
*
*
*
*
Language
ISSN
1465-7392
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. [ABSTRACT FROM AUTHOR]