Figure 2. G1–S regulatory modules and relevance to cancer.

Control over the G1–S transition is coordinated by distinct regulatory modules that are dysregulated in cancer. a | Initially, mitogenic signals impinge on cyclin-dependent kinase 4 (CDK4) or CDK6 activity through multiple mechanisms, including the induction of cyclin D1 (CycD1) gene (CCND1) expression, protein stability and assembly of the CDK–Cyc complex. These steps can be individually antagonized, or the induction of CDK4 and CDK6 inhibitors (that is, the inhibitor of CDK4 (INK4) family of proteins) can function to prevent complex assembly and to inhibit assembled complexes b | The net activation state of CDK4 and CDK6 initiates the phosphorylation of the tumour suppressor retinoblastoma protein (RB) that contributes to activation and release of the E2F family of transcription factors. E2F proteins control the expression of a multitude of positive-acting factors that are critical for progression through the S phase and the G2–M transition. Multiple mechanisms lead to RB inactivation in cancer, such as mutations, aberrant phosphorylation or protein sequestration. c | E2Fs and additional signals drive the expression and activation of CDK2–CycE and CDK2–CycA complexes, which contribute to DNA replication and further phosphorylation of RB. Deregulation of this activity is found in cancer through amplification of E-type cyclins or loss of CDK inhibitors. CCN, cyclin; CDC, cell division cycle; CDT1, chromatin licensing and DNA replication factor 1; CIP, CDK-interacting protein; KIP, kinase inhibitory protein; MAD2L1, MAD2 mitotic arrest deficient-like 1; MCM, minichromosome maintenance complex component; PLK1, polo-like kinase 1.