Insulin regulates the activity and/or amount of over 40 different proteins. In some cases activity is modified by covalent modification of an existing amount of protein. In other cases insulin affects the rate of synthesis of specific proteins. Until recently little was known about this process. Fror the past four years we have been investigating how insulin decreases the rate of synthesis of phosphoenolypyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. We have found that insulin selectively inhibits transcription of the PEPCk gene. This results, in sequence, in decreased nuclear mRNAPEPCK, decreased cytoplasmic mRNAPEPCK and decreased PEPCK synthesis. Three groups of studies will be used to investigate how this novel action of insulin is accomplished. These include: 1) Studies of how insulin and related molecules affect PEPCK gene transcription in cultured H4IIE hematoma cells; 2) A search for the substrance or process that couples the interaction of insulin and its receptor to this nuclear effect; and 3) An analysis of this action of insulin at the PEPCK gene level. These studies will use assays that measure the initiation and elongation of PEPCK gene transcription and will involve fusion gene analysis to search for DNA sequences involved in this effect. These studies are important because this the first example of a specific effect of insulin at the gene level. These studies should provide a prototype for other examples which are sure to follow.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK035107-05
Application #
3233352
Study Section
Biochemistry Study Section (BIO)
Project Start
1984-07-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
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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