The c-myc oncogene encodes a potent inducer of cell proliferation, but it is also a potent trigger of a contradictory apoptotic process. We will investigate the relative roles of proliferation versus apoptosis in intestinal cancer using a unique model in which a switchable form of the c-myc protein is targeted to mouse intestinal epithelium. In effect, the transgenic mice will have an oncogenic mutation that we can switch on and off, enabling us to investigate the consequences on intestinal morphology and neoplasia of c-myc activation. These studies will provide new insights into the role of apoptosis in suppressing cancer and the value of c-myc as a potential therapeutic target in intestinal cancer. Cancer is a multi-step process that can occur by a number of oncogenes acting together in a process called oncogene cooperation.
Some oncogenes stimulate activation of cellular pathways leading to uncontrolled cell division.
These inappropriate activation signals usually trigger cellular defense genes, tumor suppressors, which neutralize the neoplastic effect of the activating oncogene by causing the cell to stop dividing or die. Inactivation of the negative effects of these tumor suppressor pathways by other oncogenes will cooperate with the activating oncogene to help generate a cancer cell. The important ART-p53 tumor suppressor pathway is perturbed in many cancer cells. The ARF and p53 genes are inactivated in many human cancers and mice lacking either the ARF or p53 gene are quite tumor prone. A number of viruses encode proteins that inactivate the ART-p53 tumor suppressor pathway after viral infection.