mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Author(s)
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.
Date Issued
2015-08-17
Date Acceptance
2015-07-20
Citation
Nature Cell Biology, 2015, 17 (9), pp.1205-1217
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
Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Medical Research Council
Identifier
https://www.nature.com/articles/ncb3225
Grant Number
511377
BB/H020527/2
MC-A654-5QB40
Subjects
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
Date Publish Online
2015-08-17