Cited by 868FOXO transcription factor regulationRedox biology and oxidative stressFibroblast Growth Factor Research

IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a

Open access
Hu, Mickey C.-T, Lee, Dung-Fang, Xia, Weiya, Golfman, Leonard S, Ou-Yang, Fu, Yang, Jer-Yen, Zou, Yiyu, Bao, Shilai +4 more·2004·Cell

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 IkappaB 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 IKKbeta or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKbeta 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.

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Crossref · 10.1016/s0092-8674(04)00302-2

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  • Mammalian forkhead family members act as tumour suppressors and regulators of mammalian stem cell lifespan.

    “There is also growing evidence that mammalian forkhead family members act as tumour suppressors and regulators of mammalian stem cell lifespan 92, 93, 94 .”

    From The common biology of cancer and ageing (2007) · cites this paper as [92]

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Authors
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.
Affiliations
The University of Texas System (US)
Corresponding author
  • Hu, Mickey C.-T
  • Hung, Mien-Chie
Venue
Cell
Publisher
Elsevier BV
Published
2004-04
Volume
117
Issue
2
Pages
225-237
ISSN
0092-8674 (ISSN-L)
OpenAlex
W1966828006
Cited by
868
References
22
Citations by year
2026: 14 · 2025: 17 · 2024: 20 · 2023: 19 · 2022: 21 · 2021: 29 · 2020: 29 · 2019: 30 · 2018: 39 · 2017: 33 · 2016: 32 · 2015: 41 · 2014: 45 · 2013: 58 · 2012: 67
FWCI
18.39
Type
journal article
Language
en
Update notices
erratum (2007-06-29)
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (P01 CA99031, R01CA058880, CA-16772, R01-CA58880, P01CA099031)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Keywords
IκB kinase, FOXO3, carcinogenesis, nuclear exclusion, protein phosphorylation, proteolysis, breast cancer, cell proliferation, cell survival
MeSH terms
Forkhead Box Protein O1, Animals, Breast Neoplasms, Carcinoma, Cell Division, Cell Nucleus, Cell Survival, Cell Transformation, Neoplastic, Cysteine Endopeptidases, DNA-Binding Proteins, Female, Humans, Mice, Nude, Multienzyme Complexes, Neoplasms, Phosphorylation, Proto-Oncogene Proteins, Transcription Factors, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, Active Transport, Cell Nucleus, Feedback, Physiological, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-akt, Mice, I-kappa B Kinase, Forkhead Transcription Factors

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