The protein kinases MEK1 and MEK2 are activated in response to mitogenic factors and oncogene products. Multiple lines of evidence have implicated these enzymes in the control of cell proliferation and survival, and mounting evidence suggests that they are also implicated in the pathogenesis of cancer. Indeed, it has been reported that constitutive activation of these enzymes is sufficient to generate tumours in mice. Moreover, numerous studies have documented the up-regulation and activation of these protein kinases in carcinomas and leukemias, providing strong rationale for targeting this pathway to treat cancer. Several inhibitors of MEK1/2 are presently undergoing Phase I/II evaluation in cancer patients. Our laboratory has recently showed that MEK1 and MEK2 are aberrantly activated in almost half of colorectal cancer cases. The objective of this research project is to define the specific roles of MEK1/MEK2 in the initiation and maintenance of colorectal cancer using mouse models.