Mutations in Fbx4 Inhibit Dimerization of the SCFFbx4 Ligase and Contribute to Cyclin D1 Overexpression in Human Cancer
Open accessAbstract
SCF(Fbx4) was recently identified as the E3 ligase for cyclin D1. We now describe cell-cycle-dependent phosphorylation and dimerization of Fbx4 that is regulated by GSK3beta and is defective in human cancer. We present data demonstrating that a pathway involving Ras-Akt-GSK3beta controls the temporal phosphorylation and dimerization of the SCF(Fbx4) E3 ligase. Inhibition of Fbx4 activity results in accumulation of nuclear cyclin D1 and oncogenic transformation. The importance of this regulatory pathway for normal cell growth is emphasized by the prevalence of mutations in Fbx4 in human cancer that impair dimerization. Collectively, these data reveal that inactivation of the cyclin D1 E3 ligase likely contributes to cyclin D1 overexpression in a significant fraction of human cancer.
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In cancer, failure of SCF(Fbx4) to dimerize blocks ubiquitination of cyclin D1, leading to cyclin D1 accumulation and transformation.
“Lack of SCF(Fbx4) dimerization in cancer prevents ubiquitination of its substrate cyclin D1, which contributes to cyclin D1 overexpression and transformation (Barbash et al, 2008).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Barbash et al, 2008
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- Authors
- Barbash, O., Zamfirova, P., Lin, D. I., Chen, X., Yang, K., Nakagawa, H., Lu, F., Rustgi, A. K., & Diehl, J. A.
- Affiliations
- University of Pennsylvania (US)
- Peking University (CN)
- Corresponding author
- Diehl, J. Alan
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 14
- Issue
- 1
- Pages
- 68-78
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2597358
- OpenAlex
- W2023040745
- Cited by
- 140
- References
- 39
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 1 · 2020: 6 · 2019: 10 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 11 · 2014: 10 · 2013: 11 · 2012: 15
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA098101, CA11360, R01CA111360, P30CA016520)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- E3 ubiquitin ligase, cyclin D1, cyclin D1 overexpression, protein dimerization, GSK3β, oncogenic transformation, human cancer
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cell Cycle, Cell Nucleus, Cell Transformation, Neoplastic, Esophageal Neoplasms, Female, Humans, Mammary Neoplasms, Experimental, Mutation, Phosphorylation, Serine, Transfection, Up-Regulation, Gene Expression Regulation, Neoplastic, Cyclins, Mice, SCID, Mice, Inbred NOD, Protein Structure, Tertiary, ras Proteins, Dimerization, Glycogen Synthase Kinase 3, NIH 3T3 Cells, F-Box Proteins, SKP Cullin F-Box Protein Ligases, Proto-Oncogene Proteins c-akt, Mice, Cyclin D
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