Using kinetic studies to uncover new Rb functions in inhibiting cell cycle progression

A well-established biological activity of the tumor suppressor Rb is blocking G₁/S cell cycle progression when reintroduced into cultured Rb-deficient tumor cells. The best understood molecular mechanism underlying this function is that Rb binds the transcription factor E2F to repress expression of S phase genes such as cyclins E and A. A recent kinetic study of this model further revealed that Rb represses Skp2 to stabilize p27, which inhibits the kinase activity associated with cyclins E and A before the decline in their protein levels, to arrest the cell cycle. This p27-stabilizing function of Rb is retained in a clinical partial penetrance Rb mutant that is biochemically inactive for E2F repression, suggesting a mechanism for Rb-mediated inhibition of tumor progression.