Combinatorial roles for pRB, p107, and p130 in E2F-mediated cell cycle control

Numerous studies have implicated the pRB family of nuclear proteins in the control of cell cycle progression. Although overexpression experiments have revealed that each of these proteins, pRB, p107, and p130, can induce a G( 1) cell cycle arrest, mouse knockouts demonstrated distinct developmental r equirements for these proteins, as well as partial functional redundancy be tween family members. To study the mechanism by which the closely related p RB family proteins contribute to cell cycle progression, we generated 3T3 f ibroblasts derived from embryos that lack one or more of these proteins (pR B(-/-), p107(-/-), p130(-/-), pRB(-/-)/p107(-/-), pRB(-/-)/p130(-/-). and p 107(-/-)/p130(-/-)), By comparing the growth and cell cycle characteristics of these cells, we have observed clear differences in the manner in which they transit through the G(1) and S phases as well as exit from the cell cy cle. Deletion of Rb, or more than one of the family members. results in a s hortening of G(1) and a lengthening of S phase, as well as a reduction in g rowth factor requirements. In addition, the individual cell lines showed di fferential regulation of a subset of E2F-dependent gene promoters, as well as differences in cell cycle-dependent kinase activity. Taken together, the se observations suggest that the closely related pRB family proteins affect cell cycle progression through distinct biochemical mechanisms and that th eir coordinated action may contribute to their diverse functions in various physiological settings.