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A complex secretory program orchestrated by the inflammasome controls paracrine senescence
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A complex secretory program orchestrated by the inflammasome controls paracrine senescence.pdf | Accepted version | 4.57 MB | Adobe PDF | View/Open |
Title: | A complex secretory program orchestrated by the inflammasome controls paracrine senescence |
Authors: | Acosta, JC Banito, A Wuestefeld, T Georgilis, A Janich, P Morton, JP Athineos, D Kang, T-W Lasitschka, F Andrulis, M Pascual, G Morris, KJ Khan, S Jin, H Dharmalingam, G Snijders, AP Carroll, T Capper, D Pritchard, C Inman, GJ Longerich, T Sansom, OJ Aznar Benitah, S Zender, L Gil, J |
Item Type: | Journal Article |
Abstract: | Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15INK4b and p21CIP1. Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo. |
Issue Date: | 1-Aug-2013 |
Date of Acceptance: | 13-May-2013 |
URI: | http://hdl.handle.net/10044/1/76687 |
DOI: | 10.1038/ncb2784 |
ISSN: | 1465-7392 |
Publisher: | Nature Research |
Start Page: | 978 |
End Page: | U221 |
Journal / Book Title: | Nature Cell Biology |
Volume: | 15 |
Issue: | 8 |
Copyright Statement: | © 2013 Macmillan Publishers Limited. All rights reserved. The final publication is available at Springer via https://doi.org/10.1038/ncb2784 |
Keywords: | Science & Technology Life Sciences & Biomedicine Cell Biology DIPLOID CELL STRAINS NF-KAPPA-B PANCREATIC-CANCER TGF-BETA TUMOR PROGRESSION GROWTH TUMORIGENESIS P16(INK4A) EXPRESSION P53 Animals Cell Line, Tumor Cellular Senescence Colonic Neoplasms Gene Expression Regulation, Neoplastic Humans Immunohistochemistry Inflammasomes Interleukin-1 Mice Models, Animal Paracrine Communication Protein Binding Signal Transduction Transforming Growth Factor beta1 Cell Line, Tumor Animals Humans Mice Colonic Neoplasms Interleukin-1 Immunohistochemistry Models, Animal Cell Aging Paracrine Communication Signal Transduction Gene Expression Regulation, Neoplastic Protein Binding Transforming Growth Factor beta1 Inflammasomes Science & Technology Life Sciences & Biomedicine Cell Biology DIPLOID CELL STRAINS NF-KAPPA-B PANCREATIC-CANCER TGF-BETA TUMOR PROGRESSION GROWTH TUMORIGENESIS P16(INK4A) EXPRESSION P53 Developmental Biology 06 Biological Sciences 11 Medical and Health Sciences |
Publication Status: | Published |
Online Publication Date: | 2013-06-16 |
Appears in Collections: | Institute of Clinical Sciences |