Revisiting retinoblastoma protein phosphorylation during the mammalian cell cycle

Abstract.

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.