Knowledge Bank

Ras is a highly conserved gene in animals that is a key component of many different cellular pathways that control proliferation, differentiation, and cell death. In its oncogenic form, Ras is implicated in approximately 30% of human cancers. Our lab has generated Drosophila cell lines that express oncogenic Ras (RasV12) in an inducible manner. When Ras expression is turned on, the cells proliferate and when Ras is turned off, the cells stop proliferating. If the cells are maintained without RU486 for about three weeks rare cells start proliferating again and form colonies from which clonal lines were derived. These clones have bypassed dependence on Ras, presumably through genetic changes that activate other growth pathways (Fig. 1). Characterizing the Ras-bypass cells in relation to the parental lines is my thesis project. Seven different Ras-bypass clones were isolated. I conducted western blot analysis to characterize signaling pathways in these clones. The pathways I examined were ERK (MAPK), though which Ras signals, and the stress pathways involving AMPK and p38. From these data I determined that in contrast to the parental lines, the Ras bypass clones do not express stress proteins in the absence of Ras expression. In future work it will be important to determine the growth pathways that are activated in these cells that allow them to continue proliferating. In cancer, bypass mechanisms are often the reason tumors no longer respond to drug treatment targeting the original oncogene driver. In the long term, I expect my results may be useful for developing new therapies that overcome drug resistance by targeting additional pathways.