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Lookup NU author(s): Dr Alessio Iannetti, Dr Adeline Ledoux, Dr Susan Tudhope, Helene Sellier, Adam Moore, Dr Simon CockellORCiD, Dr Elaine WillmoreORCiD, Professor Neil PerkinsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
There are two major pathways leading to induction of NF-kappa B subunits. The classical (or canonical) pathway typically leads to the induction of RelA or c-Rel containing complexes, and involves the degradation of I kappa B alpha in a manner dependent on I kappa B kinase (IKK) beta and the IKK regulatory subunit NEMO. The alternative (or non-canonical) pathway, involves the inducible processing of p100 to p52, leading to the induction of NF-kappa B2(p52)/RelB containing complexes, and is dependent on IKK alpha and NF-kappa B inducing kinase (NIK). Here we demonstrate that in primary human fibroblasts, the alternative NF-kappa B pathway subunits NF-kappa B2 and RelB have multiple, but distinct, effects on the expression of key regulators of the cell cycle, reactive oxygen species (ROS) generation and protein stability. Specifically, following siRNA knockdown, quantitative PCR, western blot analyses and chromatin immunoprecipitation (ChIP) show that NF-kappa B2 regulates the expression of CDK4 and CDK6, while RelB, through the regulation of genes such as PSMA5 and ANAPC1, regulates the stability of p21WAF1 and the tumour suppressor p53. These combine to regulate the activity of the retinoblastoma protein, Rb, leading to induction of polycomb protein EZH2 expression. Moreover, our ChIP analysis demonstrates that EZH2 is also a direct NF-kappa B target gene. Microarray analysis revealed that in fibroblasts, EZH2 antagonizes a subset of p53 target genes previously associated with the senescent cell phenotype, including DEK and RacGAP1. We show that this pathway provides the major route of crosstalk between the alternative NF-kappa B pathway and p53, a consequence of which is to suppress cell senescence. Importantly, we find that activation of NF-kappa B also induces EZH2 expression in CD40L stimulated cells from Chronic Lymphocytic Leukemia patients. We therefore propose that this pathway provides a mechanism through which microenvironment induced NF-kappa B can inhibit tumor suppressor function and promote tumorigenesis.
Author(s): Iannetti A, Ledoux AC, Tudhope SJ, Sellier H, Zhao B, Mowla S, Moore A, Hummerich H, Gewurz BE, Cockell SJ, Jat PS, Willmore E, Perkins ND
Publication type: Article
Publication status: Published
Journal: PLoS Genetics
Year: 2014
Volume: 10
Issue: 9
Online publication date: 25/09/2014
Acceptance date: 28/07/2014
Date deposited: 08/12/2014
ISSN (print): 1553-7390
ISSN (electronic): 1553-7404
Publisher: Public Library of Science
URL: http://dx.doi.org/10.1371/journal.pgen.1004642
DOI: 10.1371/journal.pgen.1004642
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