ArticleScientific reports2022
CDK4/6 initiates Rb inactivation and CDK2 activity coordinates cell-cycle commitment and G1/S transition.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed.
- Not only as a Cullin3 ligase adaptor, SPOP may also act as a molecular bridge.Genes & diseases · 2027Review
- A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.Annals of medicine · 2026Review
- Next-generation CDK inhibitors in HR+/HER2- breast cancer.The Journal of clinical investigation · 2026Review
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- Comparative Functional Effects of Abemaciclib and Arcyriaflavin A inInternational journal of molecular sciences · 2026Article
- Rewiring the Molecular Interplay of CDK4/6 Inhibitors in Lung Cancer: From Cell Cycle Control to Immune Microenvironment Remodeling.International journal of molecular sciences · 2026Review
- Complex Regulation of RETINOBLASTOMA-RELATED's Interactions With E2Fs via Phosphorylation.Plant, cell & environment · 2026Article
- CDC7 and APC/CNature communications · 2026Article
- CDK4/6 Inhibitor-Induced Senescence in Cancer: Mechanisms and Therapeutic Implications.Cancers · 2026Review
- From Ethnobotany to Pharmacognosy: A Review ofPlants (Basel, Switzerland) · 2026Review
- CYTH4 Facilitates Renal Cell Carcinoma via Enhancing Proliferation and Likely Immune Evasion.Biomolecules · 2026Article
- Cell-cycle targeted cancer therapy: clinical advances, biological gaps, and the emergence of selective CDK4 inhibitors.Journal of hematology & oncology · 2026Review
- Polystyrene Nanoplastics at an Environmentally Relevant Concentration Promote Ovarian Cancer Progression via CDK4/6-Dependent Signaling.Environment & health (Washington, D.C.) · 2026Article
- Tumor cell cycle regulation: integrated perspective of stage characteristics, regulatory networks, and signaling pathway intervention strategies.Molecular biomedicine · 2026Review
- Novel Cell Cycle Inhibitors Decrease Primary and Metastatic Breast Cancer Growth In Vivo.Cancers · 2026Article
- GATA4-targeted compounds induce apoptosis and diminish viability of hepatoblastoma cells.PloS one · 2026Article
- Tumor suppressor network dysregulation in neuroblastoma: molecular mechanisms and precision therapeutic opportunities.Frontiers in cell and developmental biology · 2026Review
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- CDK2 inhibition enhances CDK4/6 inhibitor antitumor activity in comprehensive breast cancer PDX model screen.NPJ breast cancer · 2025Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors.
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Abstract
External signaling controls cell-cycle entry until cells irreversibly commit to the cell cycle to ensure faithful DNA replication. This process is tightly regulated by cyclin-dependent kinases (CDKs) and the retinoblastoma protein (Rb). Here, using live-cell sensors for CDK4/6 and CDK2 activities, we propose that CDK4/6 initiates Rb inactivation and CDK2 activation, which coordinates the timing of cell-cycle commitment and sequential G1/S transition. Our data show that CDK4/6 activation induces Rb inactivation and thereby E2F activation, driving a gradual increase in CDK2 activity. We found that rapid CDK4/6 inhibition can reverse cell-cycle entry until CDK2 activity reaches to high levels. This suggests that high CDK2 activity is required to initiate CDK2-Rb positive feedback and CDK4/6-indpendent cell-cycle progression. Since CDK2 activation also facilitates initiation of DNA replication, the timing of CDK2-Rb positive feedback is coupled with the G1/S transition. Our experiments, which acutely increased CDK2 activity by cyclin E1 overexpression, indicate that cells commit to the cell cycle before triggering DNA replication. Together, our data suggest that CDK4/6 inactivates Rb to begin E2F and CDK2 activation, and high CDK2 activity is necessary and sufficient to generate a bistable switch for Rb phosphorylation before DNA replication. These findings highlight how cells initiate the cell cycle and subsequently commit to the cell cycle before the G1/S transition.
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