Notch signaling mediates secondary senescence

Teo, Y. V. et al. (2019) Notch signaling mediates secondary senescence. Cell Reports, 27(4), 997-1007.e5. (doi: 10.1016/j.celrep.2019.03.104) (PMID:31018144) (PMCID:PMC6486482)

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Abstract

Oncogene-induced senescence (OIS) is a tumor suppressive response to oncogene activation that can be transmitted to neighboring cells through secreted factors of the senescence-associated secretory phenotype (SASP). Currently, primary and secondary senescent cells are not considered functionally distinct endpoints. Using single-cell analysis, we observed two distinct transcriptional endpoints, a primary endpoint marked by Ras and a secondary endpoint marked by Notch activation. We find that secondary oncogene-induced senescence in vitro and in vivo requires Notch, rather than SASP alone, as previously thought. Moreover, Notch signaling weakens, but does not abolish, SASP in secondary senescence. Global transcriptomic differences, a blunted SASP response, and the induction of fibrillar collagens in secondary senescence point toward a functional diversification between secondary and primary senescence.

Item Type:Articles
Additional Information:K.K. was supported by the Wellcome Trust (105641/Z/14/Z). T.C. was supported by a Chancellor’s Fellowship held at the University of Edinburgh. N.P was supported by a Ph.D studentship funded by the Wellcome Trust Sanger Institute (206194) and the Royal Thai Government. N.O. was supported by MRC (MC_PC_15075). N.N. lab was partially supported by IDeA grant P20GM109035 (Center for Computational Biology of Human Disease) from NIH NIGMS and grant 1R01AG050582-01A1 from NIH NIA. Y.V.T was funded by the American Federation for Aging Research. T.G.B. was funded by the Wellcome Trust (WT107492Z). C.K. was supported by CRUK Beatson Institute Core funding. P.D.A. was funded by P01 grant (AG031862) and by CRUK (C10652/A16566). Work in the Green laboratory was supported by Bloodwise, CRUK, Wellcome Trust. J.-C.A. was supported by CRUK (C47559/A16243).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bird, Dr Thomas and Kirschner, Dr Kristina and Adams, Professor Peter and Kiourtis, Christos
Creator Roles:
Kirschner, K.Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review and editing, Funding acquisition, Resources, Supervision, Visualization, Project administration, Data curation
Authors: Teo, Y. V., Rattanavirotkul, N., Olova, N., Salzano, A., Quintanilla, A., Tarrats, N., Kiourtis, C., Müller, M., Green, A. R., Adams, P. D., Acosta, J.-C., Bird, T. G., Kirschner, K., Neretti, N., and Chandra, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cell Reports 27(4):997-1007.e5
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
510448Epigenetics of Aging and Age-associated diseases : Epigenetic regulation of senescence and agingPeter AdamsNational Institutes of Health (NIH)5P01AG031862-08RI CANCER SCIENCES
625582Senescence-associated chromatin changes a barrier to tumor progression.Peter AdamsCancer Research UK (CRUK)16566ICS - EPIGENETICS