INVESTIGATING THE GENETICS OF PROGRAMMED CELL DEATH
IN THE YEASTS, SACCHAROMYCES CEREVISIAE AND CANDIDA ALBICANS
Apoptosis is both an important physiological process and a significant anti-tumor defense mechanism in multicellular organisms. Human cells that bypass apoptosis in response to oncogenic stimuli can undergo malignant transformation. Some have even called the ability to evade programmed cell death a “hallmark of cancer”. Significantly, there is good evidence that apoptosis contributes to the anti-tumor activity of many chemotherapeutic drugs and that mutations that disable apoptosis can result in multi-drug resistance.
The budding yeast, Saccharomyces cerevisiae, has served as a useful model for complex physiological processes of metazoan cells including apoptosis. Much work has gone into attempting to describe the molecular mechanisms that drive this process. For the past eight years, our laboratory at Providence College has investigated the genetics of programmed cell death in budding yeast.
First, we have generated mutants lacking UTH1 and BXI1, two genes linked with programmed cell death in yeast, and showed that they have phenotypes associating them with the cell wall and with the endoplasmic reticulum respectively. We are in the process of uncovering the function of Bxi1p in the yeast unfolded protein response (UPR). Papers describing our results have been published in FEMS Yeast Research and PLoS ONE, which are available on the Publications page of this website.
Second, we are elucidating the mechanism of action of sulforaphane (SFN), a member of a class of antioxidants known as isothiocyanates that is found in broccoli and other cruciferous vegetables. Other laboratories have implicated SFN in programmed cell death in mammalian cells. Genetic screens to identify SFN-resistant mutants are ongoing projects in our lab. Our data suggests that the vacuole is involved in SFN resistance in yeast.
Recently, we have begun to investigate the genetics of programmed cell death in the yeast, Candida albicans, one of the most commonly encountered human pathogens in the world.
Overall, our laboratory exploits the primary advantage of the yeast system over its mammalian counterpart as a model system for programmed cell death: Yeast cells are amenable to genetic analysis that allows investigators to identify rapidly molecular pathways underlying a biological process.
Saccharomyces cerevisiae cells stained with solophenyl flavine to visualize the chitin levels in their cell walls. Research in our lab suggests that cell wall integrity in yeast modulates the cell’s response to agents that induce programmed cell death. [Image taken by Shawn Davidson ’10]