Fine Tuning the Cell Cycle: Activation of the Cdk1 Inhibitory Phosphorylation Pathway during Mitotic Exit
- 15 March 2009
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 20 (6), 1737-1748
- https://doi.org/10.1091/mbc.e08-07-0771
Abstract
Inactivation of cyclin-dependent kinase (Cdk) 1 promotes exit from mitosis and establishes G1. Proteolysis of cyclin B is the major known mechanism that turns off Cdk1 during mitotic exit. Here, we show that mitotic exit also activates pathways that catalyze inhibitory phosphorylation of Cdk1, a mechanism previously known to repress Cdk1 only during S and G2 phases of the cell cycle. We present evidence that down-regulation of Cdk1 activates Wee1 and Myt1 kinases and inhibits Cdc25 phosphatase during the M to G1 transition. If cyclin B/Cdk1 complex is present in G1, the inhibitory sites on Cdk1 become phosphorylated. Exit from mitosis induced by chemical Cdk inhibition can be reversed if cyclin B is preserved. However, this reversibility decreases with time after mitotic exit despite the continued presence of the cyclin. We show that this G1 block is due to phosphorylation of Cdk1 on inhibitory residues T14 and Y15. Chemical inhibition of Wee1 and Myt1 or expression of Cdk1 phosphorylation site mutants allows reversal to M phase even from late G1. This late Cdk1 reactivation often results in caspase-dependent cell death. Thus, in G1, the Cdk inhibitory phosphorylation pathway is functional and can lock Cdk1 in the inactive state.Keywords
This publication has 37 references indexed in Scilit:
- Myt1 protein kinase is essential for Golgi and ER assembly during mitotic exitThe Journal of cell biology, 2008
- Mitosis persists in the absence of Cdk1 activity when proteolysis or protein phosphatase activity is suppressedThe Journal of cell biology, 2007
- Cdk1 is sufficient to drive the mammalian cell cycleNature, 2007
- Requirements for Cdk7 in the Assembly of Cdk1/Cyclin B and Activation of Cdk2 Revealed by Chemical Genetics in Human CellsMolecular Cell, 2007
- The reversibility of mitotic exit in vertebrate cellsNature, 2006
- Identification and Comparative Analysis of Multiple Mammalian Speedy/Ringo ProteinsCell Cycle, 2004
- Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cellsThe Journal of cell biology, 2004
- Differential Regulation of Cdc2 and Cdk2 by RINGO and CyclinsPublished by Elsevier BV ,2001
- Potent Inhibition of Cdc2 Kinase Activity by the Flavonoid L86-8275Biochemical and Biophysical Research Communications, 1994
- Universal control mechanism regulating onset of M-phaseNature, 1990