Grant: Operating Grant

Every living organism must control precisely when and how its cells divide. Complex molecular mechanisms inside the cell have evolved to enforce this regulation. In humans, mutations in some of the genes involved in these processes can result in uncontrolled and unrestricted proliferation known as cancer. Understanding the molecular mechanisms that regulate cell division in normal cells, and how they are altered in cancer cells, allows the design of drugs that modify the activity of targeted molecules to stop the division of cancer cells. Moreover, because evolution has conserved these very important genes and proteins across organisms, we can exploit the relative simplicity and laboratory convenience of model organisms in our research. My model of choice is the fruitfly Drosophila melanogaster. The Polo-like kinases are a family of proteins that are crucial in regulating cell division. These proteins promote cell division by modifying the structure and activity of other proteins. The first protein of this family to be discovered was the Polo kinase of Drosophila. In humans, the equivalent protein (Plk1) is often overactive in cancer cells. For this reason, drugs that can inhibit Plk1 are being developed to treat cancer. Unfortunately, we do not yet fully understand the mechanisms by which the Polo-like kinases are controlled in the cell. I have recently found two additional kinase proteins that appear to regulate Polo in the fly. I will use genetic, biochemical, molecular and cell biological approaches to elucidate how these kinases control Polo, and to assess the biological consequences of failures in these mechanisms. This knowledge will improve our molecular understanding of cancer and suggest new ways to interfere with Polo-like kinases as a way to treat cancer.