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Herranz, N.* ; Gallage, S.* ; Mellone, M.* ; Wuestefeld, T.* ; Klotz, S.* ; Hanley, C.J.* ; Raguz, S.* ; Acosta, J.C.* ; Innes, A.J.* ; Banito, A.* ; Georgilis, A.* ; Montoya, A.* ; Wolter, K.* ; Dharmalingam, G.* ; Faull, P.* ; Carroll, T.* ; Martínez-Barbera, J.P.* ; Cutillas, P.* ; Reisinger, F. ; Heikenwälder, M. ; Miller, R.A.* ; Withers, D.* ; Zender, L.* ; Thomas, G.J.* ; Gil, J.*

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

Nat. Cell Biol. 17, 1205-1217 (2015)
Publ. Version/Full Text Supplement DOI
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Quellenangaben Volume: 17, Issue: 9, Pages: 1205-1217 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Reviewing status Peer reviewed