The p53 and RB tumour-suppressor pathways

p53 and RB are at the heart of the two main tumour-suppressor pathways that control cellular responses to potentially oncogenic stimuli. Each pathway consists of several upstream regulators and downstream effectors. For simplicity, only four main components in each pathway are shown. Similarly, the pathways interact at several points, two of which are shown. In the p53 pathway, signals such as DNA damage induce the ARF (also known as p14 in humans and p19 in mice) product of the CDKN2A locus. ARF increases p53 levels by sequestering MDM2, which facilitates the degradation and inactivation of p53. p53 has both transactivation and transrepression activity, and so controls the transcription of numerous genes. Among the p53 target genes are WAF1, an inhibitor of cyclin-dependent protein kinases (CDKs) that, among other activities, causes cell-cycle arrest, and BAX, which promotes apoptotic cell death. In the RB pathway, stress signals such as oncogenes induce INK4A, the other product of the CDKN2A locus. INK4A inhibits CDKs that phosphorylate, and therefore inactivate, RB during the G1 phase of the cell cycle. RB also controls the expression of numerous genes, although it does so primarily by recruiting transcription factors and chromatin remodelling proteins. One downstream consequence of RB activity is the inhibition of E2F activity, which is important for the transcription of several genes that are required for progression through the G1 and S phases of the cell cycle. RB also regulates p53 activity through a trimeric p53-MDM2-RB complex.