Interdisciplinary Training

David Winkler, Ph.D.

Kilworth Fellow

The Role of Ras Activated Signal Transduction In Environmental And Genetic Carcinogenesis

For the last three years, as a postdoc in Dr. Jon Cooper's Lab in Basic Science, I have been studying how the Ras oncogene interacts with and activates Raf-1 and PI3 kinase effector proteins, and how these effectors contribute to the transformation by Ras in tissue culture cells. It is clear from a large body of work that the activation of Ras by mutation is an initiating event for carcinogenesis in the mouse, and that mutationally activated Ras genes are present in a large proportion of human cancers. With the interdisciplinary funding I have initiated a study of the status of Ras signaling in mouse liver and skin tumors. The goal of this analysis is to determine the contributions of the Raf and PI3 kinase signal transduction pathways to Ras carcinogenesis: are they activated in tumors constitutively as might be expected, or perhaps downregulated by enforced activation? Does the signaling of these pathways change during tumor progression? Dr. Chris Kemp's Lab in Cancer Biology (PHS) studies the role of cell cycle and DNA repair genes in mouse tumor developement. I am currently generating preliminary results examining Ras signaling in tumors generated by the Kemp Lab. I am learning a considerable amount about the difficulties encountered when taking techniques that are optimized using relatively simple tissue culture systems and transfering them to the study of more complex whole tissue systems. I am finding the process quite rewarding, especially as I find that my expectations developed by studies in tissue culture cells are revised as I obtain my initial results.