| Mitotically proliferating cells generally coordinate rates of cell cycle progression with rates of cell growth (i.e., mass accumulation). Studies in several model systems indicate that rates of cell growth dictate rates of cell cycle progression, although the mechanisms that coordinate growth with the cell cycle are poorly understood. Mammalian Ras genes, along with many oncogenes, regulate cell proliferation in bath developing tissues and tumor cells, and most studies suggest that they do so by regulating the cell cycle. In contrast, I find that Drosophila Ras primarily regulates rates of cell growth in the developing wing, and that expression of an activated form of Ras (RasV12) or dMyc is not sufficient to accelerate rates of cell division. I show that RasV12 promotes cell growth and G1/S progression by increasing dMyc protein levels and by activating dPI3K via separate effector pathways. I further demonstrate that the ability of RasV12 and dMyc to drive progression through the GUS transition of the cell cycle likely results from post-transcriptional upregulation of the GI/S rate-limitor Cyclin E. In experiments using a ras null allele, I demonstrate that endogenous Ras is required to maintain normal dMyc protein levels, but not dPI3K activity, during wing development. Thus, Ras may only utilize PI3K as an effector when mutationally activated, such as in RasV12-transformed cells. Analyses of the effects of RAS V12 on cell identity demonstrate that upregulation of dMyc and regulation of cell identity are separate effects of Ras/Raf/MAPK signaling. Finally, I show that Ras regulates expression of DE-cadherin, which may explain the ability of Ras to regulate cell adhesion, vein/intervein compartment boundary formation, and vein cell fate specification in the developing wing. My results indicate that a primary function of several oncogenes in vivo is to regulate cell growth, and that their effects on the cell cycle may be secondary consequences of growth promotion. The ability of RasV12 to drive growth via both dMyc and dPI3K, and to regulate cell fate and cell adhesion, provide a basis for understanding the potency of Ras as an oncogene as well as the synergy between Ras and other growth-promoting oncogenes in cancer. |
