Please use this identifier to cite or link to this item: https://doi.org/10.1038/onc.2012.517
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dc.titleNon-canonical Notch signaling activates IL-6/JAK/STAT signaling in breast tumor cells and is controlled by p53 and IKKα/IKKβ
dc.contributor.authorJin, S.
dc.contributor.authorMutvei, A.P.
dc.contributor.authorChivukula, I.V.
dc.contributor.authorAndersson, E.R.
dc.contributor.authorRamsköld, D.
dc.contributor.authorSandberg, R.
dc.contributor.authorLee, K.L.
dc.contributor.authorKronqvist, P.
dc.contributor.authorMamaeva, V.
dc.contributor.authorÖstling, P.
dc.contributor.authorMpindi, J.-P.
dc.contributor.authorKallioniemi, O.
dc.contributor.authorScrepanti, I.
dc.contributor.authorPoellinger, L.
dc.contributor.authorSahlgren, C.
dc.contributor.authorLendahl, U.
dc.date.accessioned2014-12-12T07:33:04Z
dc.date.available2014-12-12T07:33:04Z
dc.date.issued2013-10-10
dc.identifier.citationJin, S., Mutvei, A.P., Chivukula, I.V., Andersson, E.R., Ramsköld, D., Sandberg, R., Lee, K.L., Kronqvist, P., Mamaeva, V., Östling, P., Mpindi, J.-P., Kallioniemi, O., Screpanti, I., Poellinger, L., Sahlgren, C., Lendahl, U. (2013-10-10). Non-canonical Notch signaling activates IL-6/JAK/STAT signaling in breast tumor cells and is controlled by p53 and IKKα/IKKβ. Oncogene 32 (41) : 4892-4902. ScholarBank@NUS Repository. https://doi.org/10.1038/onc.2012.517
dc.identifier.issn09509232
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/115834
dc.description.abstractNotch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression, leading to activation of autocrine and paracrine Janus kinase/signal transducers and activators of transcription signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent of the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two proteins in the nuclear factor (NF)-κB signaling cascade, IKKα and IKKβ (inhibitor of nuclear factor kappa-B kinase subunit alpha and beta, respectively), as well as by p53. Activation of IL-6 by Notch required IKKα/IKKβ function, but interestingly, did not engage canonical NF-κB signaling, in contrast to IL-6 activation by inflammatory agents such as lipopolysaccharide. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, and restoring wild-type p53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced transcriptomes from p53 wild-type and -mutated breast tumor cell lines differed extensively, and for a subset of genes upregulated by Notch in a p53-mutant cell line, this upregulation was reduced by wild-type p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKα/IKKβ in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output. © 2013 Macmillan Publishers Limited All rights reserved.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1038/onc.2012.517
dc.sourceScopus
dc.subjectBCL
dc.subjectbreast cancer
dc.subjectCytokine
dc.subjectestrogen receptor
dc.subjectinflammation
dc.subjecttumor stroma
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.description.doi10.1038/onc.2012.517
dc.description.sourcetitleOncogene
dc.description.volume32
dc.description.issue41
dc.description.page4892-4902
dc.description.codenONCNE
dc.identifier.isiut000325717800005
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