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

作者：Herranz, Nicolas; 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; Martinez-Barbera, Juan Pedro; Cutillas, Pedro; Reisinger, Florian; Heikenwalder, Mathias; Miller, Richard A.; Withers, Dominic; Zender, Lars; Thomas, Gareth J.; Gill, Jesus^*

来源：Nature Cell Biology, 2015, 17(9): 1205-+.

DOI：10.1038/ncb3225

• GENETICALLY HETEROGENEOUS MICE
• ONCOGENE-INDUCED SENESCENCE
• EXTENDS LIFE-SPAN
• NF-KAPPA-B
• CELLULAR SENESCENCE
• MESSENGER-RNA
• PATHWAY ACTIVATION
• LEUKEMIA-CELLS
• CANCER
• RAPAMYCIN

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.

• 出版日期2015-9