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

Title: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Authors: Herranz, N
Gallage, S
Mellone, M
Wuestefeld, T
Klotz, S
Hanley, CJ
Raguz, S
Acosta, JC
Innes, AJ
Banito, A
Georgilis, A
Montoya, A
Wolter, K
Dharmalingam, G
Faull, P
Carroll, T
Martinez-Barbera, JP
Cutillas, P
Reisinger, F
Heikenwalder, M
Miller, RA
Withers, D
Zender, L
Thomas, GJ
Gill, J
Item Type: Journal Article
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.
Issue Date: 17-Aug-2015
Date of Acceptance: 20-Jul-2015
URI: http://hdl.handle.net/10044/1/32445
DOI: 10.1038/ncb3225
ISSN: 1476-4679
Publisher: Nature Publishing Group
Start Page: 1205
End Page: 1217
Journal / Book Title: Nature Cell Biology
Volume: 17
Issue: 9
Copyright Statement: © 2015 Macmillan Publishers Limited. All rights reserved
Sponsor/Funder: Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Medical Research Council
Funder's Grant Number: 511377
BB/H020527/2
MC-A654-5QB40
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
GENETICALLY HETEROGENEOUS MICE
ONCOGENE-INDUCED SENESCENCE
EXTENDS LIFE-SPAN
NF-KAPPA-B
CELLULAR SENESCENCE
MESSENGER-RNA
PATHWAY ACTIVATION
LEUKEMIA-CELLS
CANCER
RAPAMYCIN
Animals
Cell Line, Tumor
Cellular Senescence
Female
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins
Mice, Nude
Neoplasm Transplantation
Phosphoproteins
Protein Biosynthesis
Protein-Serine-Threonine Kinases
Proteome
TOR Serine-Threonine Kinases
Cell Line, Tumor
Animals
Humans
Mice, Nude
Protein-Serine-Threonine Kinases
Intracellular Signaling Peptides and Proteins
Phosphoproteins
Proteome
Neoplasm Transplantation
Protein Biosynthesis
Female
HEK293 Cells
TOR Serine-Threonine Kinases
Cellular Senescence
Developmental Biology
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2015-08-17
Appears in Collections:Department of Immunology and Inflammation
Institute of Clinical Sciences
Faculty of Medicine