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 specification throughout development, and the loss-of-function phenotype of Ras1 suggests 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 (RAS1V12) during Drosophila imaginal disc development is sufficient to drive ectopic cell proliferation and hyperplastic tissue growth. In addition, expression of RAS1V12 induces widespread cell death in the imaginal discs, including cells not expressing the transgene, which results in ablation of adult structures. Loss-of-function mutations in the genes encoding RAF, MEK, MAPK and KSR dominantly suppress RAS1V12-induced cell proliferation. Furthermore, two RAS effector loop mutations (E37G and Y40C) that block the RAS-RAF interaction, also suppress RAS1V12-induced proliferation, consistent with a requirement for the MAPK cascade during the RAS1 mitogenic response. These two RAS effector loop mutants, however, retain some activity and can act synergistically with a MAPK gain-of-function mutation, suggesting that RAS1 may also act through signaling pathway(s) distinct from the MAPK cascade.
Karim
F D
FD
Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
Rubin
G M
GM
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002454:Cell Differentiation; D002455:Cell Division; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000254:growth & development*; D005123:Eye / Q000196:embryology / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D017344:Genes, Insect; D011905:Genes, ras; D019476:Insect Proteins / Q000502:physiology; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D019476:Insect Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins