Mammalian CDK Inhibitors as Targets of Ubiquitinization in Cancer

Within the last 10 years, several studies have clearly demonstrated that disruption of cell cycle control is one of the most frequent alterations in tumor cells leading to uncontrolled cell proliferation and tumor development (1). The commitment of eukaryotic cells to enter the DNA synthetic (S) phase of the cell cycle occurs at the so-called restriction point (R) late in G1 phase and is governed by a series of proteins called cyclins, which function as positive regulatory subunits of a family of cyclin-dependent protein kinases (CDKs) (2). Each cyclin binds to and activates specific CDKs thus controlling the progression of cells through the cell cycle. While CDKs are constitutively expressed with respect to cell cycle phases, cyclin levels oscillate, being regulated mainly at the transcriptional level but also by protein degradation via the ubiquitin proteasome pathway (1). The activity of cyclin/CDK complexes is further regulated by both positive and negative phosphorylation events (3), as well as their association with specific inhibitory proteins (2).