DIFFERENTIAL CELL-CYCLE EFFECTS INDUCED BY E2F1 MUTANTS

Expression of two types of transactivation-defective E2F1 mutants in h uman Rb--/- tumor cells led to an increase in the proportion of cells in the G(1) phase of the cell cycle as determined by FAGS analysis. Ex periments revealed two different mechanisms of action. One mutant type induced a G(1) arrest after the restriction point, with cells phenoty pically at a cell cycle stage later than G(1). The action of this muta nt was, at least in part, dependent on specific DNA binding and was ov er-ridden by coexpression of its wild-type counterpart. The other muta nt type, which is defective in DNA binding, slowed the G(1) progressio n and restored a checkpoint for cell cycle withdrawal. The G(1) phase withdrawal of these tumor cells allowed the initiation of skeletal mus cle cell differentiation. Thus, E2F1 appears to have two different fun ctions before and after the cell cycle restriction point. This report also may provide a basis for a gene therapy approach for certain human cancers.