ECTOPIC EXPRESSION OF ACTIVATED RAS1 INDUCES HYPERPLASTIC GROWTH AND INCREASED CELL-DEATH IN DROSOPHILA IMAGINAL TISSUES

The Drosophila Ras1 gene is required for proper cell fate specificatio n throughout development, and the loss-of-function phenotype of Ras1 s uggests an additional role in cell proliferation or survival, A direct role for RAS1 in promoting cell proliferation, however, has not been established, We show that expression of an activated form of RAS1 (RAS 1(V12)) during Drosophila imaginal disc development is sufficient to d rive ectopic cell proliferation and hyperplastic tissue growth. In add ition, expression of RAS1(V12) induces widespread cell death in the im aginal discs, including cells not expressing the transgene, which resu lts in ablation of adult structures. Loss-of-function mutations in the genes encoding RAF, MEK, MAPK and KSR dominantly suppress RAS1(V12)-i nduced cell proliferation. Furthermore, two RAS effector loop mutation s (E37G and Y40C) that block the RAS-RAF interaction, also suppress RA S1(V12)-induced proliferation, consistent with a requirement for the M APK cascade during the RAS1 mitogenic response. These two RAS effector loop mutants, however, retain some activity and can act synergistical ly with a MAPK gain-of-function mutation, suggesting that RAS1 may als o act through signaling pathway(s) distinct from the MAPK cascade.