Fig. 1
From: Recent advances of highly selective CDK4/6 inhibitors in breast cancer
Regulation and function of CDK4/6 in cell cycle progression. Active complex of CDK4/6 and cyclin D phosphorylates and inactivates RB protein and then releases transcription factor E2F, triggering the up-regulation of E2F-responsive gene which promotes cell proliferation with cell cycle G1/S transition. The combination of CDK4/6 and cyclin D can also phosphorylates transcription factor FOXM1, resulting in the FOXM1-dependent expression of gene which protects cancer cells from cell cycle block. The kinase activity of CDK4/6 is suppressed by p16INK4A and pharmacologic CDK4/6 inhibitors including palbociclib, ribociclib and abemaciclib. Cyclin D is regulated by multiple pathways such as ER/PR/AR, NF-kB, MAPKs, STATs, Wnt/β-catenin, and PI3K/AKT/mTOR. Besides, CDK2/cyclin E also participates in the RB phosphorylation. CDK2/cyclin A complex increases in stages S, G2, and M, while CDK1/Cyclin A/B complex mediates the transition from G2 to M stage