NOTCH1 mediates a switch between two distinct secretomes during senescence

M Hoare, Y Ito, TW Kang, MP Weekes… - Nature cell …, 2016 - nature.com
Nature cell biology, 2016nature.com
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 …
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.
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