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Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle

Gravells, P; Tomita, K; Booth, A; Poznansky, J; Porter, AC; (2013) Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle. Human Molecular Genetics , 22 (14) pp. 2842-2851. 10.1093/hmg/ddt133. Green open access

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Abstract

Cyclin-dependent kinase 1 (Cdk1) controls cell proliferation and is inhibited by promising anticancer agents, but its mode of action and the consequences of its inhibition are incompletely understood. Cdk1 promotes S- and M-phases during the cell-cycle but also suppresses endoreduplication, which is associated with polyploidy and genome instability. The complexity of Cdk1 regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation. Here, we have used chemical genetics in a human cell line to address these issues. We rescued cells lethally depleted of endogenous Cdk1 with an exogenous Cdk1 conferring sensitivity to one ATP analogue inhibitor (1NMPP1) and resistance to another (RO3306). At no 1NMPP1 concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for Cdk1 are not simply controlled by different Cdk1 activity thresholds. We also rescued RO3306-resistant clones using exogenous Cdk1 without inhibitory phosphorylation sites, indicating that the mitotic surge of Cdk1 activity is dispensable for cell proliferation. These results suggest that the basic mammalian cycle requires at least some qualitative changes in Cdk1 activity and that quantitative increases in activity need not be rapid. Furthermore, the viability of cells that are unable to undergo rapid Cdk1 activation, and the strong association between endoreduplication and impaired proliferation, may place restrictions on the therapeutic use of a Cdk1 inhibitors.

Type: Article
Title: Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddt133
Publisher version: http://dx.doi.org/10.1093/hmg/ddt133
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Animals, CDC2 Protein Kinase, Cell Cycle, Cell Cycle Proteins, Cell Division, Cell Line, Tumor, Cell Proliferation, Cell Survival, G2 Phase, Humans, Mitosis, Protein Kinases, Pyrazoles, Pyrimidines, Xenopus, Xenopus Proteins
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/1393786
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