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NOTCH1 mediates a reciprocal switch between two distinct secretomes during senescence

ABSTRACT: Senescence, a persistent form of cell cycle arrest, is often associated with a diverse secretome, which provides complex downstream functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence (OIS) is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, whilst 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. Because enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared to 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.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Yagnesh Umrania

LAB HEAD: Masashi Narita

PROVIDER: PXD004168 | Pride | 2016-08-03

REPOSITORIES: Pride

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