Cdk2-KO Mouse

Cdk2, or Cyclin-dependent kinase 2, is a core cell-cycle kinase. It phosphorylates numerous substrates to drive cell-cycle progression, interacting with cyclins such as Cyclin E to promote the G1/S transition [2,3]. Cdk2 is involved in various biological processes including DNA replication, DNA damage response, and intracellular transport [2]. Its over-activation has been associated with multiple cancers, making it an attractive therapeutic target [1,2,4].

Genetic models, such as the Cdk2 -/- mice, have shown that while CDK1 can compensate for the loss of Cdk2 in the knockout mice, acute inhibition of Cdk2 leads to a rapid loss of substrate phosphorylation, which rebounds within hours [1]. Also, upon Cdk2 inhibition, cells can adapt through the back-stopping activity of CDK4/6, which sustains the proliferative program by maintaining Rb1 hyperphosphorylation, active E2F transcription, and cyclin A2 expression, enabling re-activation of Cdk2 in the presence of drug [1]. In aneuploid cancer cells, Cdk2 inhibition disorders centrosome stoichiometry, causing multipolarity, anaphase catastrophe, and apoptotic death, while having differential effects in normal alveolar epithelial cells [5].

In summary, Cdk2 is crucial for cell-cycle regulation and is involved in multiple biological processes. Studies using gene-knockout models have revealed its role in cancer-related processes, such as cell-cycle adaptation and centrosome regulation in aneuploid cancer cells. Understanding Cdk2's functions through these models provides insights into potential therapeutic strategies for cancers where Cdk2 is hyperactivated [1,5].

References:

1. Arora, Mansi, Moser, Justin, Hoffman, Timothy E, Miller, Nichol, Spencer, Sabrina L. 2023. Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. In Cell, 186, 2628-2643.e21. doi:10.1016/j.cell.2023.05.013. https://pubmed.ncbi.nlm.nih.gov/37267950/

2. Tadesse, Solomon, Anshabo, Abel T, Portman, Neil, Caldon, C Elizabeth, Wang, Shudong. 2019. Targeting CDK2 in cancer: challenges and opportunities for therapy. In Drug discovery today, 25, 406-413. doi:10.1016/j.drudis.2019.12.001. https://pubmed.ncbi.nlm.nih.gov/31839441/

3. Fagundes, Rafaela, Teixeira, Leonardo K. 2021. Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability. In Frontiers in cell and developmental biology, 9, 774845. doi:10.3389/fcell.2021.774845. https://pubmed.ncbi.nlm.nih.gov/34901021/

4. Zeng, Yangjie, Ren, Xiaodong, Jin, Pengyao, Li, Zhiyu, Wu, Min. 2024. Inhibitors and PROTACs of CDK2: challenges and opportunities. In Expert opinion on drug discovery, 19, 1125-1148. doi:10.1080/17460441.2024.2376655. https://pubmed.ncbi.nlm.nih.gov/38994606/

5. Chen, Zibo, Liu, Xi, Kawakami, Masanori, Narayan, Kedar, Dmitrovsky, Ethan. 2023. CDK2 inhibition disorders centrosome stoichiometry and alters cellular outcomes in aneuploid cancer cells. In Cancer biology & therapy, 24, 2279241. doi:10.1080/15384047.2023.2279241. https://pubmed.ncbi.nlm.nih.gov/38031910/