Promiscuity rules? The dispensability of cyclin E and Cdk2

Abstract

The canonical view of the mammalian cell cycle arose from studies of cultured cells rather than mutant organisms. It depicts the many complexes of cyclin and Cdk (cyclin/Cdk) as fulfilling unique and essential steps that dictate the sequential order of cell cycle events. Recent analyses of knockout mice challenge this view. Cdk2 and cyclin E, long thought to be essential, are largely dispensable. Here, we discuss the phenotypes of these and other cyclin/Cdk mutants in genetically tractable metazoa (mouse, fly, and nematode) and explore possible reasons behind similarities and differences among experimental systems and cell types.

Fig. 1

A canonical view of regulators that control entry into S phase. The rise in cyclin D levels and associated kinase activities results in partial phosphorylation of pocket proteins (Rb, p107, p130) and partial activation of the transcription factor E2F. This allows for synthesis of cyclin E and a rise in associated Cdk2 activity. At least three roles in the G₁ to S transition have been ascribed to cyclin E/Cdk2: (i) further phosphorylation and inactivation of the “pocket” proteins allowing for E2F-dependent transcription of S-phase genes, (ii) phosphorylation of the Cdk inhibitor p27, and (iii) phosphorylation and activation of proteins involved in DNA synthesis. Cyclin A/Cdk2 may be able to substitute for cyclin E/Cdk2 in some, but not all, of these roles.