Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence

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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.

Vyšlo v časopise: Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004642
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004642

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