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Hyperactivation of cyclin A-CDK induces centrosome overduplication and chromosome tetraploidization in mouse cells.
- Source :
-
Biochemical & Biophysical Research Communications . Apr2021, Vol. 549, p91-97. 7p. - Publication Year :
- 2021
-
Abstract
- Mammalian cyclin A-CDK (cyclin-dependent kinase) activity during mitotic exit is regulated by two redundant pathways, cyclin degradation and CDK inhibitors (CKIs). Ectopic expression of a destruction box-truncated (thereby stabilized) mutant of cyclin A in the mouse embryonic fibroblasts nullizygous for three CKIs (p21, p27, and p107) results in constitutive activation ("hyperactivation") of cyclin A-CDK and induces rapid tetraploidization, suggesting loss of the two redundant pathways causes genomic instability. To elucidate the mechanism underlying teraploidization by hyperactive cyclin A-CDK, we first examined if the induction of tetraploidization depends on specific cell cycle stage(s). Arresting the cell cycle at either S phase or M phase blocked the induction of tetraploidization, which was restored by subsequent release from the arrest. These results suggest that both S- and M-phase progressions are necessary for the tetraploidization by hyperactive cyclin A-CDK and that the tetraploidization is not caused by chromosome endoreduplication but by mitotic failure. We also observed that the induction of tetraploidization is associated with excessive duplication of centrosomes , which was suppressed by S-phase but not M-phase block, suggesting that hyperactive cyclin A-CDK promotes centrosome overduplication during S phase. Time-lapse microscopy revealed that hyperactive cyclin A-CDK can lead cells to bypass cell division and enter pseudo-G1 state. These observations implicate that hyperactive cyclin A-CDK causes centrosome overduplication, which leads to mitotic slippage and subsequent tetraploidization. • Many cancers show overexpression of cyclin A and low expression of CDK inhibitors. • Loss of both cyclin degradation and CDK inhibitors hyperactivates cyclin A-CDK. • Hyperactive cyclin A-CDK induces overduplication of centrosomes in S phase. • Centrosome overduplication leads cells to bypass cell division (mitotic slippage), resulting in tetraploidy • Hyperactivation of cyclin A-CDK could contribute to polyploidy in tumorigenesis. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CYCLINS
*CHROMOSOMES
*CELL cycle
*TETRAPLOIDY
*MICE
*CELL division
Subjects
Details
- Language :
- English
- ISSN :
- 0006291X
- Volume :
- 549
- Database :
- Academic Search Index
- Journal :
- Biochemical & Biophysical Research Communications
- Publication Type :
- Academic Journal
- Accession number :
- 149364465
- Full Text :
- https://doi.org/10.1016/j.bbrc.2021.02.079