Abstract
Abstract Cyclin dependent kinases (CDKs) drive progression through the eukaryotic cell cycle, making them an attractive target for cancer therapeutics. In particular, CDK2 is thought to regulate mammalian S-phase entry and progression, and frequently shows increased activity in a variety of tumors. Surprisingly, recent studies using conventional genetic approaches suggest that CDK2 is dispensable for cellular proliferation, both during normal development and in malignant cell lines. Here we use an alternative chemical genetic approach to determine whether acute ablation of CDK2 activity has the same affect as genetic deletion. We have replaced the endogenous CDK2 allele in mouse embryonic fibroblasts (MEFs) with a mutant analogue sensitive CDK2 allele, allowing us to selectively inactivate CDK2 using bulky ATP analogs. In contrast to genetically deleting CDK2, the acute inhibition of CDK2 resulted in severe defects in proliferation of non-transformed MEFs, as well as MEFs that were transformed using various oncogenes. These findings reveal a requirement for CDK2 in mammalian cell proliferation and suggest its potential as a therapeutic target in tumor cells. Citation Information: Cancer Res 2009;69(23 Suppl):C68.
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