Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis.
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Abstract
Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2-deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogene-transformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy.
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USP7 upregulation may promote oncogenesis via cyclin A2 deregulation.
“As cyclin A2 deregulation is associated with aberrant cell proliferation (Gopinathan et al., 2014), these findings suggest another way in which USP7 upregulation may promote oncogenesis.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Gopinathan et al., 2014
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- Authors
- Gopinathan, L., Tan, S. L. W., Padmakumar, V. C., Coppola, V., Tessarollo, L., & Kaldis, P.
- Affiliations
- Agency for Science, Technology and Research (SG)
- National Cancer Institute (US)
- Corresponding author
- Kaldis, Philipp
- Venue
- Cancer Research
- Published
- 2014-07-14
- Volume
- 74
- Issue
- 14
- Pages
- 3870-3879
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4102624
- OpenAlex
- W2166466732
- Cited by
- 123
- References
- 36
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 11 · 2023: 6 · 2022: 15 · 2021: 22 · 2020: 14 · 2019: 16 · 2018: 9 · 2017: 5 · 2016: 7 · 2015: 8 · 2014: 2
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- American Association for Cancer Research
- National Institutes of Health
- Institute of Molecular and Cell Biology
- Biomedical Research Council
- National Cancer Institute (Z01SC010367)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- cyclin A2, CDK2, CDK1, cell cycle, carcinogenesis, cell proliferation, premature senescence, hepatocellular carcinoma, cell cycle inhibitors, conditional knockout mice
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Enzyme Activation, Fibroblasts, Liver Neoplasms, CDC2 Protein Kinase, Cellular Senescence, Gene Deletion, Tumor Burden, Cell Proliferation, Cyclin-Dependent Kinase 2, Mice, Gene Knockdown Techniques, Cyclin A2
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