The cell cycle is broadly divided into four sequential phases: G1 (pre-DNA synthesis), S (DNA synthesis), G2 (pre-division), and M (cell division). The key regulator of the G1-S transition is the cyclin D-CDK4/6-INK4-Rb pathway. CDK4 and CDK6 share 71% amino acid identity and have largely overlapping functions. Both kinases are expressed in most cell types—albeit to different extents—and both can partner with all three D-type cyclins (D1, D2, and D3). Upon activation by mitogenic signaling pathways, D-type cyclins associate with CDK4 or CDK6. These active cyclin D-CDK4/6 complexes phosphorylate Rb, and thereby promote dissociation of the transcriptionally repressive Rb-E2F complex. The released E2F transcription factors are then free to activate genes required for entry into S phase and DNA replication. CDK4/6 activity is regulated by the INK4 family of proteins (p16INK4A, p15INK4B, p18INK4C, and p19INK4D) and by the Cip and Kip family (particularly p21CIP1 and p27KIP1). The INK4 proteins inhibit cyclin D-CDK4/6 activity by directly binding to the CDK. Of the four INK4 proteins, p16INK4A appears to be particularly important for tumor suppression. p21CIP1 and p27KIP1 have context-dependent positive and negative effects on CDK4/6 activity; both can stabilize cyclin D-CDK4/6 complexes and both possess CDK4/6-inhibitory activity under certain conditions, creating a complex system of regulation. Due to the importance of CDK4/6 activity in regulating cell proliferation and the mechanisms by which this pathway is known to be activated in cancer, selective inhibition of CDK4/6 inhibitors has emerged as an attractive therapeutic strategy.
Hamilton E, Infante J R. Targeting CDK4/6 in patients with cancer[J]. Cancer treatment reviews, 2016, 45: 129-138.