[Frontiers in Bioscience 16, 2206-2223, June 1, 2011]

An extended Myc network contributes to glucose homeostasis in cancer and diabetes

Christopher W. Peterson, Donald E. Ayer

Huntsman Cancer Institute,Department of Oncological Sciences,University of Utah,Room 4365,2000 Circle of Hope,Salt Lake City, UT 84112-5550

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. An expanded Myc network - the basics
3.1. MondoA and ChREBP
4. Metabolic reprogramming in cell proliferation
4.1. Myc and metabolic reprogramming
4.2. Myc and glucose utilization
4.3. Myc and glutaminolysis
4.4. Myc and mitochondrial function
5. Myc and insulin resistance
6. TXNIP and ARRDC4 are key MondoA and ChREBP effectors
6.1. TXNIP function in metabolism
6.2. TXNIP function in cell growth
7. MondoA and glutaminolysis
8. Mitochondrial dysfunction contributes to skeletal muscle insulin resistance
9. ChREBP and metabolism
10. MondoA and metabolism
11. MondoA and ChREBP function in cell proliferation
12. Potential cooperation between the members of extended Myc network
13. Summary and perspective
14. Acknowledgements
15. References

1. ABSTRACT

The Myc network of transcription factors plays pleiotropic roles in normal and pathological cell function. The canonical Myc network controls how the essential nutrients glucose and glutamine are utilized inside cells. The Myc network carries out this function by upregulating glucose and glutamine transporters and key enzymes in the glycolytic or glutaminolytic pathways. The Myc network also coordinates cellular utilization of glucose and glutamine in biosynthetic pathways by directly regulating mitochondrial mass and activity. We present an argument for the existence of an "extended" Myc network comprised of two related transcription factors MondoA and ChREBP. Both MondoA and ChREBP sense glycolytic flux and are the principal regulators of glucose-dependent transcription in their respective tissues, skeletal muscle and liver. MondoA also senses glutaminolytic flux into the tricarboxylic acid cycle and appears to coordinate the utilization of glucose and glutamine by regulating expression of thioredoxin interacting protein. Current data suggest that the extended Myc network regulates the cellular response to changes in nutrient availability and may be altered in cancer and insulin resistance.