Simplified views of the pRB and p53 pathways. The cdk4 and cdk6 kinases are positively regulated by G1 cyclins such as the D-type cyclins and negatively regulated by cdk inhibitors such as p16/INK4A. Cdk4 and Cdk6 phosphorylate, and thus inhibit, the retinoblastoma protein (pRB). pRB forms complexes with members of the E2F transcription factor family. These complexes repress transcription from E2F-responsive promoters. p53 is a sequence-specific DNA-binding protein that transcriptionally activates target genes such as p21/WAF1 and BAX. HDM2 silences the p53 transcriptional activation domain and targets p53 for degradation. ARF antagonizes HDM2. As indicated by the dashed lines, these apparently linear pathways are subject to cross-talk, which links them into a more complex regulatory network.