The focus of this project is to determine how several hormones, each with a unique mechanism of action, interact to regulate the expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene. A central theme conerns the inhibition of PEPCK gene transcription by insulin. Since PEPCK catalyzes a rate-controlling step in gluconeogenesis, faculty regulation of this gene by insulin could contribute to the excessive hepatic glucose production that is characteristic of non-insulin dependent diabetes mellitus. Our studies have other implications. We have discovered that several hormones regulate the PEPCK gene through a short segment of DNA that is associated with several transcription factors. None of these hormones/effectors employs an exclusive hormone response element; the elements we have identified are pleiotropic in that they participate in the response to more than one hormone. This led us to propose that this portion of the PEPCK gene promoter is a ~metabolic control domain~ which provides an integrated response, mediated by several effectors, that ensures the proper set point for gluconeogenesis.
Two Specific Aims, each with several subtopics, are presented as an extension of our on-going research program.
Aim 1 : """"""""Analysis of Insulin Action on PEPCK Gene Transcription,"""""""" concerns the purification and characterization of the insulin response element binding protein (IREB), cDNA and gene; the characterization of the multicomponent insulin receptor to the IRU.
Aim 2 : """"""""Analysis of the PEPCK Gene Glucocorticoid Response Unit (GRU)"""""""" concerns an analysis of glucocorticoid receptor (GR) glucocorticoid response element (GRE) binding; an analysis of the functional domains and targets of the accessory factors (AFs) that play a central role in the multicomponent GRU; the nature of the interaction between GR and creb, the cyclic AMP response role in the multicomponent GRU; the nature of the interaction between GR and CREB, the cycli AMP response element binding protein; and an analysis of the mechanism of action of the AF's on GR binding to the GRE.
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