IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

Mickey C.T. Hu, Dung Fang Lee, Weiya Xia, Leonard S. Golfman, Fu Ou-Yang, Jer Yen Yang, Yiyu Zou, Shilai Bao, Norihisa Hanada, Hitomi Saso, Ryuji Kobayashi, Mien Chie Hung

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704 Scopus citations

Abstract

Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IκB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKβ or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKβ promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.

Original languageEnglish (US)
Pages (from-to)225-237
Number of pages13
JournalCell
Volume117
Issue number2
DOIs
StatePublished - Apr 16 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Hu, M. C. T., Lee, D. F., Xia, W., Golfman, L. S., Ou-Yang, F., Yang, J. Y., Zou, Y., Bao, S., Hanada, N., Saso, H., Kobayashi, R., & Hung, M. C. (2004). IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell, 117(2), 225-237. https://doi.org/10.1016/S0092-8674(04)00302-2