Conditional ablation of Ikkb inhibits melanoma tumor development in mice

Jinming Yang, Ryan Splittgerber, Fiona E. Yull, Sara Kantrow, Gregory D. Ayers, Michael Karin, Ann Richmond

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    61 Scopus citations

    Abstract

    Several lines of evidence suggest that tumor cells show elevated activity of the NF-κB transcription factor, a phenomenon often resulting from constitutive activity of IκB kinase β (IKKβ). However, others have found that loss of NF-κB activity or IKKβ is tumor promoting. The role of NF-κB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKβ in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRasV12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf-/- mice with melanocyte-specific deletion of Ikkb were protected from HRasV12-initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkβ-mediated NF-κB activity.

    Original languageEnglish (US)
    Pages (from-to)2563-2574
    Number of pages12
    JournalJournal of Clinical Investigation
    Volume120
    Issue number7
    DOIs
    StatePublished - Jul 1 2010

    ASJC Scopus subject areas

    • Medicine(all)

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  • Cite this

    Yang, J., Splittgerber, R., Yull, F. E., Kantrow, S., Ayers, G. D., Karin, M., & Richmond, A. (2010). Conditional ablation of Ikkb inhibits melanoma tumor development in mice. Journal of Clinical Investigation, 120(7), 2563-2574. https://doi.org/10.1172/JCI42358