IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a
Open accessAbstract
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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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 .”
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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
- bronze
- doi.org
- Licence
- 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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