The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Oxygen is an important environmental and developmental signal that regulates cellular energetics, growth, and differentiation. Despite its central role in nearly all higher life processes, the molecular mechanisms for sensing oxygen levels and the pathways involved in transducing this information remain largely unknown. Research in my laboratory focuses on the identification of cellular oxygen sensors and the events involved in eliciting adaptive responses at the level of gene expression. Our experimental approach combines molecular, genetic, biochemical, and physiological studies.

Our current studies on oxygen-sensing pathways focus on the role of heme-and hemo-proteins, which have been implicated as effector or sensory elements in a diverse array of organisms (bacteria to humans). For these studies, we are using a simple eukaryotic model that is amenable to genetic manipulation and biochemical analyses: the yeast Saccharomyces cerevisiae. In yeast, the intracellular levels and activities of hundreds of proteins are oxygen-responsive. Several heme-dependent trans-acting factors regulate the transcription of oxygen-dependent genes, but the precise function of heme is not known. Currently, we are determining if heme functions as an obligate ligand or a redox-sensitive prosthetic group for these transcription factors or upstream elements. In addition, we recently found that the transcription of several oxygen-dependent nuclear-encoded genes responds to changes in the redox state of hemoprotein(s) in the mitochondrial respiratory chain. We are now trying to identify redox-sensitive trans-acting factors and the cis-sites in the promoters of these genes and determine the nature of the cross-talk between the mitochondria and nucleus.

Finally, despite the similarities in oxygen-sensing pathways among different taxa, there are differences in effector molecules and pathways whose physiological significance has yet to be determined. After gaining a better understanding of these pathways in lower eukaryotic cells, we plan to examine similar pathways in both hypoxia-tolerant and hypoxia-intolerant higher eukaryotes. Ultimately, we hope to provide an integrative picture of the evolution of oxygen sensing and insight into the genetic and biochemical framework that provides the physiological plasticity necessary for organisms to respond and adapt to variable oxygen environments.