Schematic of the retinoblastoma tumor suppressor pathway. Diverse mitogenic and oncogenic signals induce the expression of D-type cyclins that activate CDK4/6. The resultant kinase activity is balanced by the CDK4/6 inhibitor p16ink4a. Typically, p16ink4a is at low levels in cells but can be induced by oncogenic or DNA damage stresses to suppress CDK4/6 activity. These signals coalesce to regulate the phosphorylation of the retinoblastoma tumor suppressor (RB). When active (unphosphorylated/hypophosphorylated), RB represses the activity of the E2F family of transcription factors and limits the expression of a program of genes required for S-phase (for example, MCM7 and Cdc6) and G2/M progression (for example, Cdk1 and cyclin B1). Phosphorylation relieves this transcriptional repression and allows for cell cycle progression. CDK, cyclin-dependent kinase; P, phosphorylated.