NOTCH1 mediates a switch between two distinct secretomes during senescence

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

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159 Citations (Scopus)
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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
Issue number9
Early online date15 Aug 2016
Publication statusPublished - Sept 2016


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