Interconnections between the 3 main pathways that regulate G1/S transition.

The 3 main pathways that regulate the G1/S checkpoint (p16^INK4a-cyclin D- CDK4-Rb, p14^ARF-MDM2-p53-p21^CIP1, and p27^KIP1-cyclin E-CDK2) are closely interconnected: cyclin D/CDK4 phosphorylates Rb, releasing E2F which itself regulates p14^ARF and, consequently, p53 activity. Activation of p53 induces p21^CIP1 that inhibits cyclin E/CDK2, closing the circle. Alterations in one or more of them alter cell cycle control and give an increasing proliferative advantage to tumoral B cells. K2, CDK2; K4, CDK4; E, cyclin E; D, cyclin D.