MUTATION OF E2F-1 SUPPRESSES APOPTOSIS AND INAPPROPRIATE S-PHASE ENTRY AND EXTENDS SURIVAL OF RB-DEFICIENT MOUSE EMBRYOS

Mice mutant for the Rb tumor suppressor gene die in mid-gestation with defects in erythropoiesis, cell cycle control, and apoptosis. We show here that embryos mutant for both Rb and its downstream target E2f-1 demonstrate significant suppression of apoptosis and S phase entry in certain tissues compared to Rb mutants, implicating E2f-1 as a critica l mediator of these effects. Up-regulation of the p53 pathway, require d for cell death in these cells in Hb mutants, is also suppressed in t he Rb/E2f-1 double mutants. However, double mutants have defects in ce ll cycle regulation and apoptosis in some tissues and die at approxima tely E17.0 with anemia and defective skeletal muscle and lung developm ent, demonstrating that E2F-1 regulation is not the sole function of p RB in development.