Regulation of metabolic reprogramming by MondoA and Thioredoxin interacting protein

Cell proliferation requires increased nutrient uptake and metabolic activities that drive macromolecular synthesis to support cell growth. While unicellular organisms proliferate when nutrients like glucose are available, this is not the case in metazoans. As glucose and other essential nutrients are readily available to cells in the context of a multicellular organism, these cells actively regulate the uptake and utilization of nutrients through elaborate signaling networks. In addition to increased nutrient uptake, proliferating cells must also reorganize their metabolic activities from primarily ATP producing to biosynthetic and ATP producing to support the doubling of cellular genomic and macromolecular content to produce two viable daughter cells. To accomplish this, metabolic reprogramming from oxidative metabolism in the mitochondria to aerobic glycolysis - the Warburg effect - occurs within the cell. Aerobic glycolysis, typically observed in rapidly proliferating tumor cells, drives synthesis of macromolecules such as lipids, protein and nucleic acids, by diverting metabolites from both glycolysis and the TCA cycle into biosynthetic pathways while maintaining ATP production. Growth factor signaling pathways orchestrate this metabolic reprogramming by directly influencing glucose uptake and activating transcriptional networks, such as Myc and HIF, to upregulate glycolytic flux. Thioredoxin interacting protein (TXNIP), a tumor suppressor and a direct and glucose-induced transcriptional target of MondoA, is a potent negative regulator of glucose uptake and glycolysis. Thus, TXNIP may inhibit cell growth and proliferation by restricting substrate availability for macromolecular synthesis. When quiescent cells are stimulated to proliferate TXNIP translation and MondoA-dependent iv TXNIP transcription are acutely downregulated in response to growth factor signaling. Ectopic MondoA and TXNIP expression restricts glucose uptake and utilization resulting in restricted cell growth and proliferation. Thus downregulation of these activities might act in cooperation with activities such as Myc upregulation to drive metabolic reprogramming in response to proliferative signals.