Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2
Open accessAbstract
Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.
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CircRNAs act as miRNA sponges by binding and inhibiting miRNAs, thereby regulating target gene expression at transcriptional and post-transcriptional levels.
“Similar to competitive endogenous RNA (ceRNA), circRNAs act as sponges to bind and inhibit the activity of miRNAs [14], thus regulating the expression of target genes at the transcriptional and post-transcriptional levels through destabilization and translational silencing of mRNAs [15].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [15]
circFoxo3 produces anti-proliferative effects and blocks cell cycle progression by weakening CDK2 activity through formation of the circFoxo3-p21-CDK2 ternary complex.
“CircFoxo3 produces anti-proliferative effects and blocks cell cycle progression by weakening the activity of cyclin-dependent kinase 2 (CDK2) through formation of the circFoxo3-p21-CDK2 ternary complex [15].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [15]
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- Authors
- Du, W. W., Yang, W., Liu, E., Yang, Z., Dhaliwal, P., & Yang, B. B.
- Affiliations
- Sunnybrook Health Science Centre (CA)
- Corresponding author
- Du, William W.
- Yang, Weining
- Yang, Burton B.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-02-09
- Volume
- 44
- Issue
- 6
- Pages
- 2846-2858
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC4824104
- OpenAlex
- W2266356262
- Cited by
- 1,699
- References
- 34
- Citations by year
- 2026: 55 · 2025: 105 · 2024: 148 · 2023: 149 · 2022: 215 · 2021: 298 · 2020: 273 · 2019: 192 · 2018: 155 · 2017: 80 · 2016: 24
- FWCI
- 78.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- circular RNA, cell cycle progression, CDK2, p21, ternary complex, cyclin-dependent kinase inhibition, cell proliferation, non-coding RNA
- MeSH terms
- Forkhead Box Protein O3, Animals, Binding Sites, Cell Cycle, Cell Line, Cell Nucleus, Cytoplasm, Fibroblasts, Gene Expression Regulation, Humans, Nucleic Acid Conformation, Organ Specificity, Protein Binding, Signal Transduction, Cyclin A, Cyclin E, RNA, Untranslated, NIH 3T3 Cells, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase 2, Mice, Forkhead Transcription Factors
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