Efficient Wnt mediated intestinal hyperproliferation requires the cyclin D2-CDK4/6 complex

Unscheduled cell division is characteristic of cancer cells [1]. As such, normal cell division is a tightly controlled process that only permits cells to divide in a timely and restricted manner. This process is directed by two classes of proteins, a group of serine/threonine kinases termed cyclin-dependent kinases (CDKs) and their activating binding partners, cyclins [2].Heterodimeric complexes of CDKs and cyclins drive all stages of the cell cycle. The G1/S phases of the cell cycle are primarily directed by the sequential phosphorylation of the retinoblastoma susceptibility protein Rb. Hypophosphorylated Rb binds to E2F and functions as a transcriptional repressor of E2F target genes. In early G1 phase, CDK4 and CDK6 are activated by D-type cyclins leading to phosphorylation of Rb. This leads to partial dissociation of the E2F/Rb complex and expression of E2F target genes required for cell cycle progression such as cyclins A and E. The accumulation of cyclin E leads to activation of CDK2 and further phosphorylation of Rb. This leads to full release of E2F, further activation of E2F targets and entry into S phase [3,4]. During S phase a complex of cyclin A-CDK2 drives S phase progression by phosphorylation of various proteins involved in DNA replication [5]. As S phase concludes, the activity of cyclin A-CDK1 initiates prophase and finally, the cyclin B-CDK1 complex contributes to completion of mitosis [6,7]. Cell cycle progression is also controlled by inhibition of cdk activity by two families of inhibitors. Cyclin D-CDK4/6 complexes are inhibited by the INK4 family (p15INK4b, p16INK4a, p18INK4c and p19INK4d) and cyclin A/B/E-CDK1/2 complexes by the Cip/Kip family (p21Cip1/Waf1/Sdi1, p27Kip1 and p57Kip2) [8].Given increased cellular proliferation is a key feature of tumourigenesis, it would be predicted that inappropriate activation of CDK/cyclin complexes would occur in cancer. This has proven to be the case, with deregulation of CDK4 and CDK6 implicated in a wi