Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes a rate-controlling step of gluconeogenesis, the process by which cells synthesize glucose from metabolic precursors. The blood glucose level is maintained within well-defined limits in part due to precise regulation of PEPCK gene expression. To emphasize the importance of PEPCK in glucose homeostasis, over expression of this enzyme in mice results in symptoms of type II diabetes mellitus, by far the most common form of diabetes in humans. Due to the importance of blood glucose homeostasis, a number of hormones regulate a set of genes (including PEPCK) in the liver that modulate the rate of glucose synthesis. The Granner laboratory has long been interested in the multihormonal regulation of the PEPCK gene, and has worked out many of the molecular mechanisms by which hormones affect gene expression. In general, hormones regulate the transcription of genes by influencing proteins (trans-acting factors) that bind to DNA elements (cis-elements) located in the promoter, near the beginning of a gene's coding sequence. Glucocorticoids, glucagon and retinoic acid all stimulate transcription of the PEPCK gene, while insulin acts to turn off the PEPCK gene, even if the gene is stimulated by other hormones.
Our lab has characterized several cis-elements (and the trans- acting factors that bind them) that are responsible for the various hormonal responses. The collection of DNA elements and associated transcription factors is called a hormone response unit (HRU). Noteworthy is the fact that some HRUs share common DNA elements, although they bind different transcription factors. This arrangement provides for the fine-tuning of PEPCK gene regulation through a versatile mechanism that provides for additivity, synergism, redundancy, dominant repression.
Rotation, thesis and postdoctoral projects concern how these hormones individually, and collectively, regulate the rate of transcription of this important gene. Emphasis is placed on how faculty regulation of this gene could contribute to the pathophysiology of diabetes.