Journal Article

NOTCH1 mediates a switch between two distinct secretomes during senescence

Salama, Rafik, Patten, Daniel A., Matheson, Nicholas J., Howat, William, Zender, Lars, Menon, Suraj, Weekes, Michael P., Antrobus, Robin, Ito, Yoko, Tomimatsu, Kosuke, Narita, Masashi, Parry, Aled J., Lehner, Paul J., Hoare, Matthew, Kang, Tae-Won, Shetty, Shishir

2016

Overview

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. Hoare et al.  find that NOTCH1 regulates the switch between two distinct senescence-associated secretomes—the TGF-β pathway and pro-inflammatory cytokines—and that its inhibition promotes clearance of oncogene-induced senescent liver cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/2 / 13/21 / 13/31 / 13/51 / 13/89 / 13/95 / 14/19 / 38 / 38/35 / 38/39 / 38/91 / 631/67 / 631/80/509 / 631/80/86 / 64/60 / 82 / 82/58 / Animals / Cancer Research / Cell aging / Cell Biology / Cell Cycle Checkpoints - physiology / Cell Line, Tumor / Cellular Senescence / Cytokines / Development and progression / Developmental Biology / Health aspects / Humans / Life Sciences / Liver tumors / Lymphocytes / Medical research / Mice, Transgenic / Oncology / Physiological aspects / Physiology / Proteins / Receptor, Notch1 - genetics / Receptor, Notch1 - metabolism / Senescence / Stem Cells / Transcription factors / Transforming Growth Factor beta - metabolism / Transforming growth factors / Tumorigenesis