Cell growth and division requires the coordination of growth factor signaling and metabolic pathways. It is quite common that this coordination is deregulated in human malignancy. For example, ectopic activation of growth factor signaling pathways is ubiquitous in cancer and drives cell growth and division. Further, cancer cells also require an elevated supply of nutrients, e.g. glucose, glutamine and amino acids, to support their high growth and division rates. A prime example of nutrient deregulation in cancer is the oncogene-dependent upregulation of glucose transporters and glycolysis. The mTORC1 complex is one signaling node where these diverse stimuli converge and the activity of this growth-promoting complex is highest in cells with abundant nutrients and engaged growth factor signaling pathways. How nutrient availability and growth signals are coordinated at the transcriptional level is poorly understood, however, our studies on the MondoA:Mlx complex indicate a prominent role for this bHLHZip factor complex in this regard. MondoA is the primary glucose- regulated transcription factor in mammalian cells, yet signals from the mitochondrial TCA cycle also control MondoA transcriptional activity. Our published data show that high rates of glutaminolysis convert MondoA from a transcriptional activator to a transcriptional repressor. MondoA's downregulation of thioredoxin interacting protein (TXNIP) creates an environment that is permissive for both glucose uptake and glycolysis. The MondoA-TXNIP regulatory circuit further coordinates cell growth as the mTORC1 complex negatively regulates this circuit. This blockage of MondoA:Mlx transcriptional activity by mTORC1, likely contributes to mTORC1's well-documented function in driving glucose uptake and glycolysis. The importance of the MondoA-TXNIP regulatory circuit is underscored by its likely tumor suppressor function in both breast, ovarian, and potentially other cancers. In this application, we propose to study on how the MondoA:Mlx complex senses and responds to the TCA cycle intermediate a-ketoglutarate. We will also determine the transcriptional networks that are activated downstream of mitochondrial status and the dependence of these networks on MondoA. Next, we will determine how the transcriptional functions of MondoA:Mlx complexes are controlled by the mTORC1 complex and the breadth of this regulation. Finally, we will examine the role of the MondoA- TXNIP circuit as a growth/tumor suppressor in breast cancer using mouse models. These studies will lead to a deeper understanding of how diverse signals from growth factor signaling pathways, mitochondrial status and nutrient availability are integrated by the MondoA:Mlx complex. Given that the deregulation of these pathways is near universal in human malignancy, our hope is that this work will provide new avenues for therapeutic intervention in cancer.

Public Health Relevance

How cells coordinate the utilization of nutrients with bioenergetic status contributes to cellular homeostasis. This coordination is often deregulated in human cancer underscoring its importance. Our lab is interested in a bHLHZip transcription factor called MondoA. MondoA is the primary glucose-regulated transcription factor in mammalian cells, yet mitochondrial status and the mTORC1 complex also regulate its activity. Here we propose to study how these different signals control the transcriptional activity of MondoA and how broadly MondoA contributes to the transcriptional programs driven by these different signals and how dysregulation of MondoA activity contributes to breast cancer.

National Institute of Health (NIH)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Krasnewich, Donna M
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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