Pocket proteins and cell cycle control

The retinoblastoma protein (pRB) and the pRB-related p107 and p130 comprise the ‘pocket protein’ family of cell cycle regulators. These proteins are best known for their roles in restraining the G1–S transition through the regulation of E2F-responsive genes. pRB and the p107/p130 pair are required for the repression of distinct sets of genes, potentially due to their selective interactions with E2Fs that are engaged at specific promoter elements. In addition to regulating E2F-responsive genes in a reversible manner, pocket proteins contribute to silencing of such genes in cells that are undergoing senescence or differentiation. Pocket proteins also affect the G1–S transition through E2F-independent mechanisms, such as by inhibiting Cdk2 or by stabilizing p27Kip1, and they are implicated in the control of G0 exit, the spatial organization of replication, and genomic rereplication. New insights into pocket protein regulation have also been obtained. Kinases previously thought to be crucial to pocket protein phosphorylation have been shown to be redundant, and new modes of phosphorylation and dephosphorylation have been identified. Despite these advances, much remains to be learned about the pocket proteins, particularly with regard to their developmental and tumor suppressor functions. Thus continues the story of the pocket proteins and the cell cycle.