To combat cancer, the underlying mechanistic abnormalities that contribute to the development of cancer have to be defined. Historically one very successful way of dissecting this process has been to examine the molecular details of transformation of cultured cells via the early region of the simian virus 40 viral genome. This region encodes three proteins, the large T(LT) antigen, small T(st) antigen and the 17k protein which is largely similar to LT. We have learned much about specific cellular components that regulate the proliferation of cells, such as the tumor suppressor proteins p53 and the retinoblastoma, by deciphering LT and 17K function but relatively little is known about st. This application will look in detail at the mechanism used by st in transformation of human epithelial cells. Preliminary studies have indicated that st directly interacts with protein phosphatase 2A to affect the phosphoinositide-3 kinase signaling pathway. I wish to dissect this interaction to get a further understanding of how st promotes the transformation of cells. I also believe these experiments have the ability to greatly further our knowledge of PP2A function in cancer and consequently have potential therapeutic implications for human tumors. ? ?
