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J. Biol. Chem., Vol. 282, Issue 7, 4301-4309, February 16, 2007

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

From the Department of Haematology and Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom

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.

Received for publication, August 17, 2006 , and in revised form, December 11, 2006.

^* This work was supported by the Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1S.

¹ These authors contributed equally to this work.

² Present address: Transplant Immunology, National Heart and Lung Institute, Imperial College London, Harefield Hospital, Harefield, Middlesex UB9 6JH, United Kingdom.

³ To whom correspondence should be addressed: Gene Targeting Group, Dept. of Haematology, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom. Tel.: 44-20-8383-8276; E-mail: andy.porter{at}imperial.ac.uk.

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