Skp2 and Skp2B team up against Rb and p53

The retinoblastoma (Rb) and the p53 pathways are two major mechanisms of tumor suppression. Disruption of these pathways is observed in most cancers. This review focuses on the description of two mechanisms by which both Rb and p53 pathways are disrupted simultaneously. First, the loss of the well known p16INK4a/p19ARF locus and second, the less well known amplification of the Skp2/Skp2B locus.The remarkable genetic organization of some loci suggests that evolution has selected mechanisms to maximize their biological impact. One example of such clever organization is the p16Ink4a/p19Arf locus. By using two distinct promoters, this locus allows the expression of two different proteins using overlapping genetic material (reviewed in [1]; the p16 protein, a cyclin-dependent kinase (cdk) inhibitor and ARF, an indirect regulator of the tumor suppressor gene p53.The cyclin dependent kinases (cdk) are a family of protein serine/threonine kinases, which control cell cycle progression through association with their regulatory subunits, known as cyclins. Cyclins are classified into a large number of subtypes including the D, E, A and B-type cyclins. Humans encode three D-type cyclins, cyclin D1, cyclin D2 and cyclin D3. D-type cyclins associate with cdk4 and 6 to promote the phosphorylation of the Retinoblastoma (Rb) protein (for review, [2]). Rb forms a complex with the E2F family of transcription factors and this represses their activity. Hyperphosphorylation of Rb results in the release of E2F, which then activates transcription of genes required for DNA replication and entry into S phase [3]. One of the early targets of E2F mediated transcription is cyclin E that, together with cdk2, acts to maintain Rb phosphorylation.Cyclin-cdk complexes are themselves regulated by two families of cdk inhibitors including p27 of the p21 family, which inhibits cyclin E-cdk2 complexes [4], and p16 of the INK4 family, which inhibits cyclin D-cdk4/6 complexes [5]. Functional disruption of t