Overview of the G1/S transition of the cell cycle. Following stimulation of proliferation, accumulation of cyclin D1-CDK4/6 complex will lead to phosphorylation of retinoblastoma protein (pRB) thus allowing E2F to promote expression of genes leading to progression from the G1 phase to the S phase of the cell cycle. Cyclin E-CDK2 allow further phosphorylation of RB creating a positive feedback loop. Intracellular or extracellular factors such as DNA damage or lack of required growth factors can influence this process in a negative fashion (e.g.: through p21 or p53).