NOTCH1 mediates a 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 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-?-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBP?. NOTCH1 and NOTCH1-driven TGF-? 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-? and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.

SUBMITTER: Hoare M 

PROVIDER: S-EPMC5008465 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature