Notch and Senescence
Cellular senescence, previously thought of as an autonomous tumour suppressor mechanism, is emerging as a phenotype and effector present throughout the life of an organism from embryogenesis to senile decline. Senescent cells have powerful non-autonomous effects upon multiple players within their microenvironment mainly through their secretory phenotype. How senescent cells co-ordinate numerous, sometimes functionally contrasting outputs through their secretome had previously been unclear. The Notch pathway, originally identified for its involvement in Drosophila wing development, has more recently been found to underpin diverse effects in human cancer. Here we discuss recent findings that suggest that Notch is intimately involved in the development of senescence and how it acts to co-ordinate the composition and functional effects of the senescence secretome. We also highlight the complex physical and functional interplay between Notch and p53, critical to both senescence and cancer. Understanding the interplay between Notch, p53 and senescence could allow us develop the therapeutics of the future for cancer and ageing.
KeywordsNOTCH Senescence SASP Secretome TGF-beta Interleukins Immune surveillance RAS
MH and MN are supported by an MRC Research Grant (MR/R010013/1). MH is supported by a CRUK Clinician Scientist Fellowship (C52489/A19924). MN is supported by a Cancer Research UK Cambridge Centre Core Grant (C14303/A17197).
- Aster JC, Pear WS, Blacklow SC (2017) The varied roles of notch in Cancer. Annu Rev Pathol 12:245–275. https://doi.org/10.1146/annurev-pathol-052016-100127 CrossRefPubMedGoogle Scholar
- Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol. https://doi.org/10.1038/nrm.2016.94
- Coppé J-P, Desprez P-Y, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol Mech Dis 5:99–118. https://doi.org/10.1146/annurev-pathol-121808-102144 CrossRefGoogle Scholar
- Jin S, Mutvei AP, Chivukula IV et al (2012) Non-canonical Notch signaling activates IL-6/JAK/STAT signaling in breast tumor cells and is controlled by p53 and IKKα/IKKβ. Oncogene. https://doi.org/10.1038/onc.2012.517
- Lim KJ, Brandt WD, Heth JA et al (2015) Lateral inhibition of Notch signaling in neoplastic cells. Oncotarget 6:1666–1677Google Scholar
- Liu Z-J, Tan Y, Beecham GW et al (2012) Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis. Atherosclerosis 225:296–303. https://doi.org/10.1016/j.atherosclerosis.2012.04.010 CrossRefPubMedPubMedCentralGoogle Scholar
- Rampias T, Vgenopoulou P, Avgeris M et al (2014) A new tumor suppressor role for the Notch pathway in bladder cancer. Nat Med. https://doi.org/10.1038/nm.3678
- Sebastian T, Johnson PF (2009) RasV12-mediated down-regulation of CCAAT/enhancer binding protein beta in immortalized fibroblasts requires loss of p19Arf and facilitates bypass of oncogene-induced senescence. Cancer Res 69:2588–2598. https://doi.org/10.1158/0008-5472.CAN-08-2312 CrossRefPubMedPubMedCentralGoogle Scholar
- Storer M, Mas A, Robert-Moreno A et al (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell. https://doi.org/10.1016/j.cell.2013.10.041
- Yatim A, Benne C, Sobhian B et al (2012) NOTCH1 nuclear Interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol Cell. https://doi.org/10.1016/j.molcel.2012.08.022