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.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Hoare M,Ito Y,Kang TW,Weekes MP,Matheson NJ,Patten DA,Shetty S,Parry AJ,Menon S,Salama R,Antrobus R,Tomimatsu K,Howat W,Lehner PJ,Zender L,Narita Mdoi
10.1038/ncb3397subject
Has Abstractpub_date
2016-09-01 00:00:00pages
979-92issue
9eissn
1465-7392issn
1476-4679pii
ncb3397journal_volume
18pub_type
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