Role of pRB dephosphorylation in cell cycle regulation

pRB, the tumor suppressor product of the retinoblastoma susceptibility gene , is regarded as one of the key regulators of the cell cycle. This protein exerts its growth suppressive effect through its ability to bind and intera ct with a variety of cellular proteins. In turn, pRB binding and interactin g ability is governed by its phosphorylation state. In recent years, this n egative growth regulatory protein has captured a great deal of attention fr om investigators around the world due to its ability to modulate the activi ty of transcription regulatory proteins, enzymes which modify chromatin, an d other cellular proteins which contribute to its complex role in mammalian cells. Hypophosphorylated pRB binds and sequesters transcription factors, most notably those of the E2F/DP family, inhibiting the transcription of ge nes required to traverse the G1 to S phase boundary. This cell cycle inhibi tory function is abrogated when pRB undergoes phosphorylation mediated by c yclin/cdk complexes following cell stimulation by mitogens. Removal of thes e phosphates appears to be carried out by a multimeric complex of protein p hosphatase type 1 (PP1) and noncatalytic regulatory subunits at the complet ion of mitosis. This dephosphorylation returns pRB to its active, growth su ppressive state. While the mechanism of pRB phosphorylation has and continu es to be extensively studied, dephosphorylation of pRB has received disprop ortionately less attention. The goal of this review is to revisit the role of pRB dephosphorylation in regulating the cell cycle. Emphasis will be pla ced on understanding the function and regulation of pRB during the cell cyc le as well as our ever-expanding notions of pRB-PP1 interaction and the mec hanism of pRB dephosphorylation at mitotic exit.