Don Ayer
Associate Professor of Oncological Sciences
B.S. University of Michigan, Ann Arbor
Ph.D. University of Colorado, Boulder
Research
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 cells. My lab is interested in how cells sense and respond to glucose and how those mechanisms are altered in cancer. Ultimately, we hope to leverage our laboratory findings to develop new prognostic and diagnostic cancer markers and identify new therapeutic targets for the treatment of cancer. 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.
Myc is a transcriptional activator that plays an important role in human malignancy; accounting for approximately 20% 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, remarkably appear to be functional analogs of Myc:Max heterodimers. We believe that MondoA:Mlx is involved in tumorigenesis and likely carries out specific aspects of Myc function.
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 current efforts are focused in two broad areas. First, we are developing mouse and worm models to examine the physiological and pathological functions of MondoA. Our focus in the pathological setting is how does MondoA contribute to cancer. Second, we are utilizing biochemical and genomic approaches to determine how MondoA senses glucose and how broadly MondoA contributes to the cellular transcriptional response to glucose.References
1. Pickett CL, Breen KT, Ayer DE (2007) The transcription activation arm of a C. elegans Myc-like network has a primary role in cell migration. Submitted
2. Kaadige MR, Ayer DE (2006) The polybasic region that follows the plant homeodomain zinc finger 1 of PF1 is necessary and sufficient for specific phosphoinositide binding. J Biol Chem 281:28831-28836
3. Shi X, Hong TY, Walter K, Ewalt M, Lan F, Kaadige MR, Lacoste N, Cayrou C, Carney D, Hung T, Pena P, Davarazou F, Cote J, Ayer DE, Shi Y, Kutateladze TG, Chua KF, Gozani O (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442:96-99
4. Sans CL, Satterwhite DJ, Stoltzman CA, Breen KT, Ayer DE (2006) MondoA:Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and regulation of glycolytic enzymes. Mol. Cell. Biol. 26:4863-4871
5. Fleischer TC, Yun UJ, Ayer DE (2003) Identification and characterization of three new components of the mSin3A corepressor complex. Mol. Cell. Biol. 23:3456-3467
6. Eilers AL, Sundwall E, Lin M, Sullivan AA, Ayer DE (2002) A novel heterodimerization domain, CRM1, and 14-3-3 control subcellular localization of the MondoA:Mlx heterocomplex. Mol. Cell. Biol. 22:8514-8526
7. Yochum GS, Ayer DE (2002) A role for the mortality factors MORF4, MRGX and MRG15 in transcriptional repression via associations with Pf1, mSin3A, and TLE. Mol. Cell. Biol. 22:7868-7876
8. Yochum GS, Ayer DE (2001) Pf1: a Novel PHD Zinc Finger Protein That Links the TLE corepressor to the mSin3A/HDAC Complex. Mol. Cell. Biol. 21:4110-4118
9. Billin AN, Coulter KL, Eilers AL, Logan JS, Ayer DE (2000) MondoA: a novel BHLHZip transcriptional activator that interacts genetically with Myc. Mol. Cell. Biol. 20:8845-8854
10. Hassig CA, Fleischer TC, Billin AN, Schreiber SL, Ayer DE (1997) Histone Deacetylase Activity is Required for Full Transcriptional Repression by mSin3A. Cell 89:341-347
