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• W4303415518 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." @default.
• W4303415518 created "2022-10-07" @default.
• W4303415518 creator A5014524055 @default.
• W4303415518 creator A5014613700 @default.
• W4303415518 creator A5037251964 @default.
• W4303415518 creator A5079398292 @default.
• W4303415518 date "2022-10-07" @default.
• W4303415518 modified "2023-09-30" @default.
• W4303415518 title "CDK4/6 initiates Rb inactivation and CDK2 activity coordinates cell-cycle commitment and G1/S transition" @default.
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• W4303415518 doi "https://doi.org/10.1038/s41598-022-20769-5" @default.
• W4303415518 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36207346" @default.
• W4303415518 hasPublicationYear "2022" @default.
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