Authors: Karl A. Merrick and Robert P. Fisher

Karl A. Merrick

Department of Structural and Chemical Biology; Mount Sinai School of Medicine; New York, NY USA; Programs in Biochemistry, Cell and Molecular Biology; Weill Cornell Graduate School of Medical Sciences; New York, NY USA
Current affiliation: Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology; Cambridge, MA USA

Robert P. Fisher

Corresponding author: robert.fisher@mssm.edu
Department of Structural and Chemical Biology; Mount Sinai School of Medicine; New York, NY USA

Abstract:
Progression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs). For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemical-genetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systems-level organization of the cell cycle, for regulation of the restriction point and G₁/S transition and for efforts to target Cdk2 therapeutically in human cancers.

Received: May 9, 2012; Accepted: May 14, 2012

Preview: