NOTCH1 mediates a switch between two distinct secretomes during senescence

Matthew Hoare, Yoko Ito, Tae Won Kang, Michael P. Weekes, Nicholas J. Matheson, Daniel A. Patten, Shishir Shetty, Aled J. Parry, Suraj Menon, Rafik Salama, Robin Antrobus, Kosuke Tomimatsu, William Howat, Paul J. Lehner, Lars Zender, Masashi Narita

Research output: Contribution to journalArticlepeer-review

150 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)979-992
Number of pages14
JournalNature Cell Biology
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

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