Revisiting retinoblastoma protein phosphorylation during the mammalian cell cycle.

It is widely accepted that phosphorylation of the retinoblastoma (Rb) protein during the G1 phase of the mammalian division cycle is a major control element regulating passage of cells into S phase and through the division cycle. The experiments supporting G1-phase-specific Rb phosphorylation and the historical development of this idea are reviewed. By making a rigorous distinction between 'growth cessation' and the phenomena of 'cell cycle exit' or 'G1-phase arrest', the evidence for the G1-phase-specific phosphorylation of Rb protein is reinterpreted. We show that the evidence for G1-phase phosphorylation of Rb rests on few experiments and a chain of reasoning with some weak links. Evidence is reviewed that growth conditions regulate the phosphorylation of Rb. A growth-regulated control system that is independent of the cell cycle explains much of the evidence adduced to support cycle-specific phosphorylation of Rb. We propose that additional experimental evidence is needed to decide whether there is a G1-phase-specific phosphorylation of Rb protein.