Professor of Oncological Sciences
Cancer Metabolism, Myc Family of Transcription Factors, Insulin Resistance, Fuel Choice
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.
- Wilde BR, Kaadige MR, Guillen KP, Butterfield, A, Welm, BE, Ayer DE (2020) Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate. Cancer and Metabolism 8 (1) 27
- Sullivan WJ, Mullen PJ, Schmid EW, Flores A, Momcilovic M, Sharpley MS, Jelinek, D, Whiteley, AE, Maxwell, MB, Wilde, BR, Banerjee, U, Coller, HA, Shackelford, DB, Braas, D, Ayer, DE, de Aguiar Vallim, TQ, Lowry, WE, Christofk, H. (2018) Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization. Cell. 175:117-32
- Ahn B., Wan S., Jaiswal N., Vega R.B., Ayer D.E., Titchenell P.M., Han X., Won K.J, and Kelly D.P. (2019) MondoA drives muscle lipid accumulation and insulin resistance. JCI Insight 5. pii: 129119. doi: 10.1172.
- Wilde, B.R., Ye, Z., Lim, T.Y., and Ayer, D.E. (2019) Cellular acidosis triggers human MondoA transcriptional activity by driving mitochondrial ATP production. Elife Feb 5;8. pii: e40199. doi: 10.7554/eLife.40199.
- Ye, Z., and Ayer, D.E. (2018) Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation. Molecular and Cellular Biology. Mol Cell Biol. Jul 23. pii: MCB.00178-18. doi: 10.1128/MCB.00178-18. EPub before print
- Schaub, F.X., Dhankani, V., Berger, A.C., Trivedi, M., Richardson, A.B., Shaw, R., Zhao, W., Zhang, X., Ventura, A., Liu, Y., Ayer, D.E., Hurlin, P.J., Cherniack, A.D., Eisenman, R.N., Bernard, B., Grandori, C., and Cancer Genome Atlas, N. (2018). Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas. Cell Syst 6, 282-300
- Shen, L., O’Shea, J.M., Cunha, S., Kaadige, M.R., Welm, A.L., and Ayer, D.E. (2015) Metabolic Reprogramming in Triple Negative Breast Cancer through Myc Regulation of TXNIP. PNAS, 172:5425-5430
- Carroll, P.A., Diolaiti, D., McFerrin, L., Gu, H., Djukovic, D., Du, J., Hurley, J., Raftery, D., Ayer, D.E. and Eisenman, R.N. (2015) Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis. Cancer Cell, 27:271-285
- Kaadige, M.R., Yang, J., Wilde, B.R., and Ayer, D.E. (2015) MondoA-Mlx transcriptional activity is limited by mTOR-MondoA interaction. Molecular and Cellular Biology 35:101-110
- Bowman, C., Ayer, D.E. and Dynlacht, B. (2014) Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nature Cell Biology 12:1202-1214
- Parmenter, T.J., Kleinschmidt, M., Kinross, K.M., Li, J., Sheppard, K.E., Cullinane, C., Pearson, R.B., Kaadige, M.R., Ayer, D.E., Ribas, A., Hicks, R.J., Johnstone, R.W., and McArthur, G.A. (2014) Response of mutant BRAF melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discovery 4:423-433
- O’Shea, J.M., and Ayer, D.E. (2013) Coordination of nutrient availability and utilization by MAX- and MLX-centered transcription networks. Cold Spring Harbor Press Perspectives in Medicine; MYC and the Pathway to Cancer, 3:a014258
- Han, K.-S., and Ayer, D.E. (2013) MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein. Biochem. J. 453:209-218
- Peterson, C.W., and Ayer, D.E. (2011) An extended Myc network contributes to glucose homeostasis in cancer and diabetes. Frontiers in Bioscience 17: 2206-2023
- Stoltzman, C.A., Kaadige, M.R., Peterson, C.W., and Ayer, D.E. (2011) MondoA senses non-glucose sugars: regulation of thioredoxin interacting protein (TXNIP) and the hexose transport curb. J Biol Chem. 286:38027-38034
- Elgort, M.G., Jiang, Y., and Ayer, D.E. (2010) Metabolic reprogramming during the G0 to G1 transition requires transcriptional and translational downregulation of Thioredoxin Interacting Protein. Genes and Cancer 1:893-907
- Chen, J.L., Merl, D., Peterson, C.W., Wu, J., Liu, P.Y., Yin, H., Muoio, D.M., Ayer, D.E., West, M., and Chi, J.-T. (2010) Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. PloS Genetics 6:1-18
- Peterson, C.W., Stoltzman, C.A., Sighinolfi, M.P., Han, K.S., and Ayer, D.E. (2010) Glucose Controls Nuclear Accumulation, Promoter Binding, and Transcriptional Activity of the MondoA:Mlx heterodimer. Mole Cell Biol 30:2887-2895
- Sloan, E.J., and Ayer, D.E. (2010) Myc, MondoA and Metabolism. Genes and Cancer 1:587-596
- Kaadige, M.R., Elgort, M.G., and Ayer, D.E. (2010) Coordination of glucose and glutamine utilization by an expanded Myc network. Transcription 1:36-40
- Peterson, CW., Stoltzman, C.A., Sighinolfi, M.P., Han, K.S., and Ayer, D.E. (2010) Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer. Mol Cell Biol 30:2887-95
- Kaadige, M.R., Looper, R.E., Kamalanaadhan, S., and Ayer, D.E. (2009) Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity. PNAS 106:14878-83
- Stoltzman, C.A., Peterson, C.W., Kaadige, M.R., Pickett, C.L., Breen, K.T., Muoio, D.M., Billin, A.N., and Ayer, D.E. (2008) Glucose-sensing by MondoA:Mlx complexes: A role for hexokinases and direct regulation of thioredoxin interacting protein. PNAS 105:6912-6917
- Pickett, C.L., Breen, K.T., and Ayer, D.E. (2007) A C. elegans Myc-like network cooperates with semaphorin and Wnt signaling pathways to control cell migration. Developmental Biology 310:226-239