Figure 1 Classical and non-classical models of the cell cycle in RB1-proficient cells Figure 1 | Classical and non-classical models of the cell cycle in RB1-proficient cells. a | Resting cells in the G0 or early G1 phase. The retinoblastoma protein, RB1, is hypophosphorylated and inhibits the transcriptional activity of the E2F family of proteins. The INK4 protein p16, acts as a brake on the activation of cyclin-dependant kinase (CDK) 4 and/or CDK6. b | The classical model of G1–S-phase transition. Mitogenic and oestrogen receptor signalling upregulates the transcription of the D-type cyclins. These D-type cyclins form a complex with CDK4/6 to phosphorylate RB1, thus partially activating the E2F-family proteins, which results in transcription of cyclins A and E, and CDK2. The phosphorylation of RB1 also induces chromatin remodelling that favours transcription (not shown). CDK4/6–cyclin D complexes sequester CDK inhibitor 1/kinase inhibitory protein (CIP/KIP) proteins, reducing their inhibitory effect on CDK2, and reducing the threshold for activation of CDK2 by E-type cyclins. As cyclin E levels rise, cyclin E complexes with CDK2 to hyperphosphorylate RB1, forming a positive feedback loop via E2F, releasing and fully activating E2F, to push the cell from G1 to S phase. c | The non-classical model of G1–S-phase transition. CDK2 is active in early G1, by forming complexes with cyclins E and potentially cyclin D directly. Both CDK4/6 and CDK2 phosphorylate RB1, and drive G1–S-phase transition. The mechanisms through which CDK2 becomes active in G1 without requiring prior CDK4/6 activation are poorly understood, although in some rapidly proliferative cells CDK2 remains active immediately after mitosis. CKI; cyclin-dependent kinase inhibitor. Turner, N. C. et al. (2016) Treating cancer with selective CDK4/6 inhibitors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.26