Don Ayer

Glucose is an ancient and universal metabolite utilized from bacteria to Man. In humans, pathological glucose sensing or utilization contributes to devastating diseases such as diabetes. Further, an elevated glycolytic rate is a near universal feature of cancer. My lab is interested in how cells sense and respond to glucose and other abundant nutrients and how these mechanisms are altered in cancer and diabetes. Ultimately, we hope to leverage our laboratory findings to develop new prognostic and diagnostic markers and identify new therapeutic targets for the treatment of these two devastating diseases. Our efforts are currently focused on how the Max network of transcription factors controls glucose metabolism normally and how its activity is altered in cancer and diabetes.

Myc is a transcriptional activator that plays an important role in human malignancy; accounting for approximately 30% of the annual U.S. cancer deaths. Myc functions only when dimerized to another transcription factor called Max. Max also interacts with the Mad family of transcriptional repressors which are potent antagonists of Myc. Via heterodimerization with members of the Myc or Mad family, Max plays a pivotal role in controlling cellular proliferation and differentiation. We have identified a novel transcription factor pair, MondoA and Mlx, that appear to be functional analogs of Myc:Max heterodimers. As such, we believe that MondoA:Mlx is has similarly pleiotropic and essential functions in controlling cell physiology and behavior.

Unlike, Myc and Max, which are constitutively nuclear proteins, MondoA and Mlx localize to the cytoplasm. However, they are not diffusely localized. MondoA and Mlx have a completely novel localization on the outer membrane of the mitochondria. MondoA shuttles between the mitochondria and the nucleus in a dynamic fashion. MondoA senses information about intracellular energy status, e.g. high glucose levels, at the mitochondrial membrane and communicates that information to the nucleus to drive adaptive changes in gene expression. MondoA:Mlx complexes regulate the expression of many key glycolytic enzymes supporting this hypothesis. Our most recent work shows that MondoA:Mlx complexes also sense glutamine, which is another abundant nutrient. Amazingly, while MondoA:Mlx functions as a transcriptional activator in the presence of glucose, it functions as a transcriptional repressor in the presence of glutamine. We are investigating that MondoA:Mlx complexes coordinate the cellular response to these two nutrients that are absolutely essential for cell growth. Our current efforts are focused in two broad areas. First, we have developed a conditional knockout allele of murine MondoA so we can examine its physiological and pathological functions in vivo. Our central focus in the pathological setting is to determine how MondoA contributes to both cancer and type II diabetes. Second, we are utilizing biochemical and genomic approaches to determine how MondoA senses glucose and glutamine and how broadly MondoA contributes to the cellular transcriptional response to changes in nutrient status.