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

Research output: Contribution to journalArticle

685 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Tumors
Carcinogenesis
Phosphotransferases
Proteolysis
Forkhead Transcription Factors
Neoplasms
Cell proliferation
Cell growth
Proteasome Endopeptidase Complex
Protein Kinases
Cell Survival
Cells
Cell Proliferation
Breast Neoplasms
Growth

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Hu, M. C. T., Lee, D. F., Xia, W., Golfman, L. S., Ou-Yang, F., Yang, J. Y., ... 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

IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. / Hu, Mickey C T; Lee, Dung Fang; Xia, Weiya; Golfman, Leonard S.; Ou-Yang, Fu; Yang, Jer Yen; Zou, Yiyu; Bao, Shilai; Hanada, Norihisa; Saso, Hitomi; Kobayashi, Ryuji; Hung, Mien Chie.

In: Cell, Vol. 117, No. 2, 16.04.2004, p. 225-237.

Research output: Contribution to journalArticle

Hu, MCT, Lee, DF, Xia, W, Golfman, LS, Ou-Yang, F, Yang, JY, Zou, Y, Bao, S, Hanada, N, Saso, H, Kobayashi, R & Hung, MC 2004, 'IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a', Cell, vol. 117, no. 2, pp. 225-237. https://doi.org/10.1016/S0092-8674(04)00302-2
Hu MCT, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004 Apr 16;117(2):225-237. https://doi.org/10.1016/S0092-8674(04)00302-2
Hu, Mickey C T ; Lee, Dung Fang ; Xia, Weiya ; Golfman, Leonard S. ; Ou-Yang, Fu ; Yang, Jer Yen ; Zou, Yiyu ; Bao, Shilai ; Hanada, Norihisa ; Saso, Hitomi ; Kobayashi, Ryuji ; Hung, Mien Chie. / IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. In: Cell. 2004 ; Vol. 117, No. 2. pp. 225-237.
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