A feature common to tumor cells is a high glycolytic rate. Increased glycolysis provides tumors with a selective growth advantage by supplying ATP to meet their high bioenergetic needs, and by supplying glucose-derived precursors required for nucleotide, amino acid and lipid biosynthesis. How tumor cells undergo the switch from respiration to glycolysis and the contribution of this switch to tumorigenesis is not fully understood. Elucidating the control mechanisms that underlie increased glycolysis in tumorigenesis will provide important insights into how misregulation of energy homeostasis contributes to cancer. Furthermore, understanding causative pathways in detail will provide additional therapeutic targets for the treatment of this devastating disease. We have discovered a new member of the basic helix-loop-helix leucine zipper family of transcription factors called MondoA. MondoA is related to the Myc proto-oncoprotein. Unlike Myc, which localizes to the nucleus, MondoA and its partner Mix localize to the outer mitochondrial membrane. Importantly, the mitochondrial localization of MondoA is not static;the protein shuttles between mitochondria and the nucleus. This shuttling suggests a role for MondoA in communicating information about intracellular bioenergetic state between these two essential organelles. Consistent with this hypothesis, when MondoA is expressed in the nucleus it upregulates glycolysis by direct transcriptional activation of rate-limiting glycolytic target genes. Further, MondoA is upregulated by oncogenic signaling pathways and regulates glycolysis in transformed diploid human fibroblasts, suggesting that it may drive the switch from respiration to glycolysis that accompanies, and is necessary for cellular transformation. We will determine the role of MondoA in regulating glycolysis and tumorigenesis in a genetically defined model of cellular transformation using loss - and gain-of-function experiments (Aim 1). We will determine how MondoA levels and glycolytic rate are dictated by upstream oncogenes such as Myc and Ras (Aim 2). We have discovered that the subcellular distribution of MondoA is controlled by a glucose-derived metabolite.
In Aim 3, we will identify this metabolite and the mechanisms by which it controls the subcellular localization of MondoA. Finally, we will determine how MondoA interacts with mitochondria by identifying its mitochondrial receptor (Aim 4).
|Wilde, Blake R; Ayer, Donald E (2015) Interactions between Myc and MondoA transcription factors in metabolism and tumourigenesis. Br J Cancer 113:1529-33|
|Carroll, Patrick A; Diolaiti, Daniel; McFerrin, Lisa et al. (2015) Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 27:271-85|
|Shen, Liangliang; O'Shea, John M; Kaadige, Mohan R et al. (2015) Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proc Natl Acad Sci U S A 112:5425-30|
|Kaadige, Mohan R; Yang, Jingye; Wilde, Blake R et al. (2015) MondoA-Mlx transcriptional activity is limited by mTOR-MondoA interaction. Mol Cell Biol 35:101-10|
|Bowman, Christopher John; Ayer, Donald E; Dynlacht, Brian David (2014) Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat Cell Biol 16:1202-14|
|Parmenter, Tiffany J; Kleinschmidt, Margarete; Kinross, Kathryn M et al. (2014) Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov 4:423-33|
|Han, Kyoung-Sim; Ayer, Donald E (2013) MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein. Biochem J 453:209-18|
|Sartor, Francesco; Jackson, Matthew J; Squillace, Cesare et al. (2013) Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes. Eur J Nutr 52:937-48|
|O'Shea, John M; Ayer, Donald E (2013) Coordination of nutrient availability and utilization by MAX- and MLX-centered transcription networks. Cold Spring Harb Perspect Med 3:a014258|
|Peterson, Christopher W; Ayer, Donald E (2011) An extended Myc network contributes to glucose homeostasis in cancer and diabetes. Front Biosci (Landmark Ed) 16:2206-23|
Showing the most recent 10 out of 17 publications