| Title: |
The oscillation of mitotic kinase governs cell cycle latches in mammalian cells. |
| Authors: |
Dragoi, Calin-Mihai1, Kaur, Ekjot2, Barr, Alexis R.2,3, Tyson, John J.4, Novák, Béla1 bela.novak@bioch.ox.ac.uk |
| Source: |
Journal of Cell Science. Feb2024, Vol. 137 Issue 3, p1-15. 15p. |
| Subject Terms: |
*MAMMALIAN cell cycle, *CELL cycle proteins, *OSCILLATIONS, *CYCLINS |
| Abstract: |
The mammalian cell cycle alternates between two phases - S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This 'toggle switch' is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 'endocycles', and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how wholegenome doubling can arise, a common event in tumorigenesis that can drive tumour evolution. [ABSTRACT FROM AUTHOR] |
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| Database: |
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