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

Nat Cell Biol. 2015 Sep;17(9):1205-17. doi: 10.1038/ncb3225. Epub 2015 Aug 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cellular Senescence
  • Female
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice, Nude
  • Neoplasm Transplantation
  • Phosphoproteins / metabolism*
  • Protein Biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteome / metabolism*
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Proteome
  • MAP-kinase-activated kinase 2
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE61130