NOTCH1 mediates a switch between two distinct secretomes during senescence

Research output: Contribution to journalArticlepeer-review

Authors

  • Matthew Hoare
  • Yoko Ito
  • Tae-Won Kang
  • Michael P Weekes
  • Nicholas J Matheson
  • Aled J Parry
  • Suraj Menon
  • Rafik Salama
  • Robin Antrobus
  • Kosuke Tomimatsu
  • William Howat
  • Paul J Lehner
  • Lars Zender
  • Masashi Narita

Colleges, School and Institutes

External organisations

  • University of Cambridge

Abstract

Senescence, a persistent form of cell-cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to 'lateral induction of senescence' through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. As enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared with typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.

Details

Original languageEnglish
Pages (from-to)979-992
Number of pages14
JournalNature Cell Biology
Volume18
Issue number9
Early online date15 Aug 2016
Publication statusPublished - Sep 2016