Author Summary Although the classical NF-κB pathway is frequently associated with the induction of cellular senescence and the senescence associated secretory phenotype (SASP), the role of the alternative NF-κB pathway, which is frequently activated in hematological malignancies as well as some solid tumors, has not been defined. We therefore investigated the role of the alternative NF-κB pathway in this process. Here we report that NF-κB2 and RelB, the effectors of the alternative NF-κB pathway, suppress senescence through inhibition of p53 activity. Using primary human fibroblasts, we demonstrate that this is accomplished through NF-κB2/RelB dependent control of a previously unknown pathway, incorporating regulation of CDK4 and 6 expression as well as regulators of p21WAF1 and p53 protein stability. Loss of NF-κB2/RelB results in suppression of retinoblastoma (Rb) tumour suppressor phosphorylation, which in turn leads to inhibition of EZH2 expression and de-repression of p53 activity. Interestingly, we find that CD40 ligand stimulation of cells from Chronic Lymphocytic Leukemia patients, which strongly induces the alternative NF-κB pathway, also induces EZH2 expression. We propose that the alternative NF-κB pathway can promote tumorigenesis through suppression of p53 dependent senescence, a process that may have relevance to cancer cells retaining wild type p53.
%0 Journal Article
%1 10.1371/journal.pgen.1004642
%A Iannetti, Alessio
%A Ledoux, Adeline C.
%A Tudhope, Susan J.
%A Sellier, Hélène
%A Zhao, Bo
%A Mowla, Sophia
%A Moore, Adam
%A Hummerich, Holger
%A Gewurz, Benjamin E.
%A Cockell, Simon J.
%A Jat, Parmjit S.
%A Willmore, Elaine
%A Perkins, Neil D.
%D 2014
%I Public Library of Science
%J PLOS Genetics
%K myown
%N 9
%P 1-20
%R 10.1371/journal.pgen.1004642
%T Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence
%U http://dx.doi.org/10.1371%2Fjournal.pgen.1004642
%V 10
%X Author Summary Although the classical NF-κB pathway is frequently associated with the induction of cellular senescence and the senescence associated secretory phenotype (SASP), the role of the alternative NF-κB pathway, which is frequently activated in hematological malignancies as well as some solid tumors, has not been defined. We therefore investigated the role of the alternative NF-κB pathway in this process. Here we report that NF-κB2 and RelB, the effectors of the alternative NF-κB pathway, suppress senescence through inhibition of p53 activity. Using primary human fibroblasts, we demonstrate that this is accomplished through NF-κB2/RelB dependent control of a previously unknown pathway, incorporating regulation of CDK4 and 6 expression as well as regulators of p21WAF1 and p53 protein stability. Loss of NF-κB2/RelB results in suppression of retinoblastoma (Rb) tumour suppressor phosphorylation, which in turn leads to inhibition of EZH2 expression and de-repression of p53 activity. Interestingly, we find that CD40 ligand stimulation of cells from Chronic Lymphocytic Leukemia patients, which strongly induces the alternative NF-κB pathway, also induces EZH2 expression. We propose that the alternative NF-κB pathway can promote tumorigenesis through suppression of p53 dependent senescence, a process that may have relevance to cancer cells retaining wild type p53.
@article{10.1371/journal.pgen.1004642,
abstract = {Author Summary Although the classical NF-κB pathway is frequently associated with the induction of cellular senescence and the senescence associated secretory phenotype (SASP), the role of the alternative NF-κB pathway, which is frequently activated in hematological malignancies as well as some solid tumors, has not been defined. We therefore investigated the role of the alternative NF-κB pathway in this process. Here we report that NF-κB2 and RelB, the effectors of the alternative NF-κB pathway, suppress senescence through inhibition of p53 activity. Using primary human fibroblasts, we demonstrate that this is accomplished through NF-κB2/RelB dependent control of a previously unknown pathway, incorporating regulation of CDK4 and 6 expression as well as regulators of p21WAF1 and p53 protein stability. Loss of NF-κB2/RelB results in suppression of retinoblastoma (Rb) tumour suppressor phosphorylation, which in turn leads to inhibition of EZH2 expression and de-repression of p53 activity. Interestingly, we find that CD40 ligand stimulation of cells from Chronic Lymphocytic Leukemia patients, which strongly induces the alternative NF-κB pathway, also induces EZH2 expression. We propose that the alternative NF-κB pathway can promote tumorigenesis through suppression of p53 dependent senescence, a process that may have relevance to cancer cells retaining wild type p53.},
added-at = {2016-11-19T01:49:57.000+0100},
author = {Iannetti, Alessio and Ledoux, Adeline C. and Tudhope, Susan J. and Sellier, Hélène and Zhao, Bo and Mowla, Sophia and Moore, Adam and Hummerich, Holger and Gewurz, Benjamin E. and Cockell, Simon J. and Jat, Parmjit S. and Willmore, Elaine and Perkins, Neil D.},
biburl = {https://www.bibsonomy.org/bibtex/2038a88662a7fa232ded47b1b2fc5c483/bgewurz},
doi = {10.1371/journal.pgen.1004642},
interhash = {e7f46f16d5ffa318747ce78e3a66dec6},
intrahash = {038a88662a7fa232ded47b1b2fc5c483},
journal = {PLOS Genetics},
keywords = {myown},
month = {09},
number = 9,
pages = {1-20},
publisher = {Public Library of Science},
timestamp = {2016-11-19T02:35:37.000+0100},
title = {Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence},
url = {http://dx.doi.org/10.1371%2Fjournal.pgen.1004642},
volume = 10,
year = 2014
}