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Notch-1 associates with IKKα and regulates IKK activity in cervical cancer cells

Oncogene volume 27, pages 5833–5844 (2008)Cite this article

Abstract

Notch-1 inhibits apoptosis in some transformed cells through incompletely understood mechanisms. Notch-1 can increase nuclear factor-kappa B (NF-κB) activity through a variety of mechanisms. Overexpression of cleaved Notch-1 in T-cell acute lymphoblastic leukemia cells activates NF-κB via interaction with the I kappa B kinase (IKK) signalosome. Concomitant activation of the Notch and NF-κB pathways has been described in a large series of cervical cancer specimens. Here, we show that wild-type, spontaneously expressed Notch-1 stimulates NF-κB activity in CaSki cervical cancer cells by associating with the IKK signalosome through IKKα. A significant fraction of tumor necrosis factor (TNF)-α-stimulated IκB kinase activity in CaSki cells is Notch-1-dependent. In addition, Notch-1 is found in the nucleus in association with IKKα at IKKα-stimulated promoters and is required for association of IKKα with these promoters under basal and TNF-α-stimulated conditions. Notch-1–IKKα complexes are found in normal human keratinocytes as well, suggesting that IKK regulation is a physiological function of Notch-1. Both Notch-1 and IKKα knockdown sensitize CaSki cells to cisplatin-induced apoptosis to equivalent extents. Our data indicate that Notch-1 regulates NF-κB in cervical cancer cells at least in part via cytoplasmic and nuclear IKK-mediated pathways.

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Acknowledgements

This work was supported by NIH grants RO1 CA084065 and 1 PO1 AG025531, and the V+Whittier Foundation (WMK). WMK holds the Walter A Richter Cancer Research Chair. We are grateful to Anna Bigas for critical reading of this manuscript and to Raphael Kopan for helpful discussion of our data and for the gift of the Notch-1/Renilla construct used for quantitative immunoprecipitation.

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Author notes

  1. L L Song and Y Peng: These authors contributed equally to this work and should be considered as co-first authors.

Authors and Affiliations

  1. Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA

    L L Song, Y Peng, J Yun, P Rizzo, A Pannuti & L Miele

  2. Department of Pathology and Skin Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA

    V Chaturvedi, J-Z Qin & B J Nickoloff

  3. Cancer Immunology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA

    S Weijzen

  4. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    W M Kast & P J B Stone

  5. Department of Molecular Biology, Institute for Scientific and Technological Research of San Luis Potosí, San Luis Potosí, Mexico

    L Santos

  6. Department of Pathology, Mexican Institute for Social Security, Mexico City, Mexico

    A Loredo

  7. Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden

    U Lendahl

  8. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

    G Sonenshein

  9. Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA, USA

    B Osborne

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Correspondence to L Miele.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Song, L., Peng, Y., Yun, J. et al. Notch-1 associates with IKKα and regulates IKK activity in cervical cancer cells. Oncogene 27, 5833–5844 (2008). https://doi.org/10.1038/onc.2008.190

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