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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK035107-15
Application #
2734034
Study Section
Endocrinology Study Section (END)
Program Officer
Laughlin, Maren R
Project Start
1984-07-01
Project End
2002-06-30
Budget Start
1998-07-20
Budget End
1999-06-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hall, Robert K; Wang, Xiaohui L; George, Leena et al. (2007) Insulin represses phosphoenolpyruvate carboxykinase gene transcription by causing the rapid disruption of an active transcription complex: a potential epigenetic effect. Mol Endocrinol 21:550-63
Herzog, Birger; Cardenas, Jessica; Hall, Robert K et al. (2006) Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem 281:99-106
Herzog, Birger; Hall, Robert K; Wang, Xiaohui L et al. (2004) Peroxisome proliferator-activated receptor gamma coactivator-1alpha, as a transcription amplifier, is not essential for basal and hormone-induced phosphoenolpyruvate carboxykinase gene expression. Mol Endocrinol 18:807-19
Wang, Xiaohui L; Herzog, Birger; Waltner-Law, Mary et al. (2004) The synergistic effect of dexamethasone and all-trans-retinoic acid on hepatic phosphoenolpyruvate carboxykinase gene expression involves the coactivator p300. J Biol Chem 279:34191-200
Waltner-Law, Mary; Duong, David T; Daniels, Marc C et al. (2003) Elements of the glucocorticoid and retinoic acid response units are involved in cAMP-mediated expression of the PEPCK gene. J Biol Chem 278:10427-35
Duong, David T; Waltner-Law, Mary E; Sears, Rosalie et al. (2002) Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter. J Biol Chem 277:32234-42
Waltner-Law, Mary E; Wang, Xiaohui L; Law, Brian K et al. (2002) Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. J Biol Chem 277:34933-40
Cusi, K J; Pratipanawatr, T; Koval, J et al. (2001) Exercise increases hexokinase II mRNA, but not activity in obesity and type 2 diabetes. Metabolism 50:602-6
Stafford, J M; Waltner-Law, M; Granner, D K (2001) Role of accessory factors and steroid receptor coactivator 1 in the regulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. J Biol Chem 276:3811-9
Stafford, J M; Wilkinson, J C; Beechem, J M et al. (2001) Accessory factors facilitate the binding of glucocorticoid receptor to the phosphoenolpyruvate carboxykinase gene promoter. J Biol Chem 276:39885-91

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