title: CPEB control of NF-kappaB nuclear localization and interleukin-6 production mediates cellular senescence.
abstract: CPEB is a sequence-specific translational regulatory RNA binding protein that mediates cellular senescence in primary mouse and human cells. CPEB knockout mouse embryo fibroblasts (MEFs) bypass senescence and synthesize large amounts of interleukin-6 (IL-6) and many other cytokines, which is not the case with either wild-type MEFs immortalized by prolonged culture or p53-deficient MEFs. CPEB regulates the production of IL-6 at both the translational and transcriptional levels; in CPEB-depleted cells, aberrant IL-6 transcription is mediated by improper NF-κB p65 phosphorylation and nuclear localization. Although IL-6 strengthens the senescence of wild-type cells, it has no effect on CPEB-deficient cells, even though they produce prodigious amounts of the cytokine. IL-6-promoted entry into senescence requires p53; CPEB knockout MEFs, however, synthesize only ∼50% of the p53 of wild-type MEFs, which is insufficient to respond to IL-6. Thus, CPEB deficiency not only increases IL-6 production but also renders the cell incapable of a senescence-promoting response.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Groppo
authors.forename: Joel D
authors.initials: JD
authors.lastname: Richter
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors
chemical_list: D020413:3' Untranslated Regions; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C490387:Cpeb1 protein, mouse; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors