Molecular Biology & Biochemistry
Cholesterol is a necessary evil. Although it is a major cause of heart disease, cholesterol is nonetheless an indispensible part of our cells and their membranes. In my laboratory, we study the biological role of cholesterol and to better understand its impact on cell growth and thereby on human health. An immediate goal of our research is to determine mechanisms of cholesterol transport within cells that are found both in humans and baker’s yeast, Saccharomyces cerevisiae. We are exploiting the power of yeast molecular genetics, cell biology, and genomics to identify and study genes required for sterol-lipid transport between membranes within yeast cells. These studies also uncovered a surprising mechanism by which a specific class of cholesterol-binding proteins affects cell polarization; a process that determines the shape and direction of growth by cells, which is defective in metastasizing cancers.
Treating yeast with cholesterol-lowering drugs (like those prescribed to people at risk for heart disease), we applied functional genomics to identify new genes that affect the transport and storage of cholesterol-like lipids within cells. In other studies, we showed that the OSBP-related protein (ORP) gene family affects the distribution of cholesterol/sterol-lipids in yeast cells. By inference, we propose that similar ORPs in humans are necessary for cholesterol transport to the cell surface, where HDL (high-density lipoprotein) mediates cholesterol removal from the cell. The yeast ORPs consists of seven genes, OSH1-OSH7. When we delete all these OSH genes from yeast, the cells die. However, using yeast molecular genetics we made yeast cells in which OSH genes can be turned-on and -off. When the OSH genes are on the cells grow, but when we turn off the OSH genes the cells have defects in intracellular ergosterol (the yeast equivalent of cholesterol) transport. These cells are also seriously misshapen, suggesting defects in cell polarization. We now know that the OSHs interact with Cdc42p and Rho1p, which are molecular switches that regulate the direction of cell growth in yeast and humans. These molecular switches in turn activate many other regulators of cell growth, including those implicated in the dissemination of solid tumours. Our research goal now is to determine how the OSHs orchestrate these important cellular functions that have obvious implications for human health.