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The oscillation of mitotic kinase governs cell cycle latches in mammalian cells.
- Source :
- Journal of Cell Science; Feb2024, Vol. 137 Issue 3, p1-15, 15p
- Publication Year :
- 2024
-
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]
- Subjects :
- MAMMALIAN cell cycle
CELL cycle proteins
OSCILLATIONS
CYCLINS
Subjects
Details
- Language :
- English
- ISSN :
- 00219533
- Volume :
- 137
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Journal of Cell Science
- Publication Type :
- Academic Journal
- Accession number :
- 175665134
- Full Text :
- https://doi.org/10.1242/jcs.261364