Related Experiment Video
Updated: Jul 19, 2026
Reconstruct Human Retinoblastoma In Vitro
Published on: October 11, 2022
Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human
Frederic Tort1, Jirina Bartkova, Maxwell Sehested
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark.
Abstract:
Loss of G(1)-S control and aberrations of the p16(Ink4a)-cyclin D1/cyclin-dependent kinase (CDK) 4(6)-pRb-E2F-cyclin E/CDK2 pathway are common in human cancer. Previous studies showed that oncogene-induced aberrant proliferation, such as on cyclin E overexpression, causes DNA damage and checkpoint activation. Here, we show that, in a series of human colorectal adenomas, those with deregulation of cyclin D1 and/or p16(Ink4a) showed little evidence of constitutive DNA damage response (DDR), contrary to cyclin E-overexpressing higher-grade cases. These observations were consistent with diverse cell culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse cells, analogous to elevated cyclin E. These results highlight differential effect of diverse oncogenic events on driving the 'cancer cell cycles' and their ability to deregulate the replication-driving CDK2 kinase and to alarm the DDR as a potential anticancer barrier in accordance with their hierarchical positions along the retinoblastoma pathway. Our data provide new insights into oncogene-evoked DDR in human tumorigenesis, with potential implications for individualized management of tumors with elevated cyclin D1 versus cyclin E, due to their distinct clinical variables and biological behavior.
Insights
Aberrant cell cycle control in cancer involves the p16-cyclin D1-CDK4/6-pRb pathway. Cyclin E overexpression triggers DNA damage response, unlike cyclin D1 deregulation, offering insights into cancer progression and treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Loss of G(1)-S cell cycle control and pathway aberrations are hallmarks of human cancer.
- Previous research linked oncogene-induced proliferation (e.g., cyclin E overexpression) to DNA damage and checkpoint activation.
Purpose of the Study:
- To investigate the differential effects of cyclin D1/p16(Ink4a) deregulation versus cyclin E overexpression on DNA damage response (DDR) in colorectal tumors and cell models.
- To elucidate the role of the retinoblastoma pathway in orchestrating DDR.
Main Methods:
- Analysis of human colorectal adenomas with varying cyclin D1, p16(Ink4a), and cyclin E expression.
- Utilizing cell culture models with specific defects in retinoblastoma pathway components (pRb, p16(Ink4a), cyclin D1, cyclin E).
- Assessing DNA damage response (DDR) activation.
Main Results:
- Colorectal adenomas with cyclin D1 and/or p16(Ink4a) deregulation showed minimal constitutive DDR.
- In contrast, higher-grade tumors with cyclin E overexpression exhibited significant DDR.
- Cell culture models confirmed that cyclin D1 overexpression or p16(Ink4a) loss did not induce DDR, whereas pRb inactivation or cyclin E elevation did.
- DDR activation correlated with the hierarchical position of defects within the retinoblastoma pathway.
Conclusions:
- Oncogenic events differentially impact cell cycle progression and DDR activation.
- Cyclin E-driven proliferation and pRb inactivation are potent inducers of DDR, acting as a potential anticancer barrier.
- Understanding these distinct pathways has implications for tailoring cancer management based on specific oncogenic drivers (cyclin D1 vs. cyclin E).
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