Non-canonical Notch signaling activates IL-6/JAK/STAT signaling in breast tumor cells and is controlled by p53 and IKKα/IKKβ

摘要: Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced contributes to tumor process less well understood. In this report, we identify proinflammatory cytokine interleukin-6 (IL-6) as a novel target cells. Enhanced upregulated IL-6 expression, leading activation of autocrine and paracrine Janus kinase/signal transducers activators transcription signaling. upregulation was mediated by non-canonical signaling, it could be effectuated cytoplasmically localized intracellular domain independent DNA-binding protein CSL. Instead, Notch-mediated controlled two proteins nuclear factor (NF)-κB cascade, IKKα IKKβ (inhibitor kappa-B kinase subunit alpha beta, respectively), p53. Activation required IKKα/IKKβ function, interestingly, did not engage canonical NF-κB contrast inflammatory agents such lipopolysaccharide. With regard p53 status, expression when mutated or lost, restoring wild-type into p53-mutated -deficient cells abrogated upregulation. Furthermore, Notch-induced transcriptomes from -mutated cell lines differed extensively, for subset genes p53-mutant line, reduced conclusion, gene, reveal roles cancer generation context-dependent diversity output.