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

研究成果: Contribution to journalArticle査読

152 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)979-992
ページ数14
ジャーナルNature Cell Biology
18
9
DOI
出版ステータス出版済み - 9 1 2016
外部発表はい

All Science Journal Classification (ASJC) codes

  • Cell Biology

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