Rescue of a Human Cell Line from Endogenous Cdk1 Depletion by Cdk1 Lacking Inhibitory Phosphorylation Sites

Cells that transiently overexpress cyclin-dependent kinase 1 lacking inhibitory phosphorylation sites (Cdk1-AF) undergo premature and catastrophic mitosis, reflecting the key role for Cdk1 in promoting a timely transit from G2 into mitosis. Conversely, cells depleted of Cdk1 undergo repeated S phase...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-02, Vol.282 (7), p.4301-4309
Main Authors: Gupta, Mita, Trott, Deborah, Porter, Andrew C.G.
Format: Article
Language:English
Subjects:
CDC2 Protein Kinase - antagonists & inhibitors
CDC2 Protein Kinase - genetics
CDC2 Protein Kinase - metabolism
Cell Cycle - drug effects
Cell Cycle - genetics
Cell Line
Enzyme Activation - drug effects
Enzyme Activation - genetics
Gene Expression
Gene Targeting
Humans
Models, Biological
Phosphorylation - drug effects
Protein Processing, Post-Translational - drug effects
Protein Processing, Post-Translational - genetics
RNA, Small Interfering - genetics
RNA, Small Interfering - pharmacology
Transcription, Genetic
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Summary:Cells that transiently overexpress cyclin-dependent kinase 1 lacking inhibitory phosphorylation sites (Cdk1-AF) undergo premature and catastrophic mitosis, reflecting the key role for Cdk1 in promoting a timely transit from G2 into mitosis. Conversely, cells depleted of Cdk1 undergo repeated S phases without intervening mitoses (endoreduplication), reflecting a role for Cdk1 in preventing premature S phases. It is not known how Cdk1 prevents entry into S phase at times in G2 when it does not promote mitosis. Also uncertain is the extent of redundancy between inhibitory phosphorylation and other mechanisms for controlling Cdk1 activity. We describe here human cells that not only tolerate stable Cdk1-AF expression but also rely on it for survival when endogenous Cdk1 is depleted. When residual endogenous Cdk1 expression is further depleted, however, proliferation of Cdk1-AF-rescued cells is inhibited. Interestingly, this inhibition is not accompanied by endoreduplication. These results are consistent with a two-threshold model for Cdk1 kinase activity, one for suppressing endoreduplication and one for promoting mitosis. They also indicate that inhibitory phosphorylation is indispensable for only a fraction of the total cellular complement of Cdk1.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M607910200