The goal of our research is to continue to explore the mechanisms of glucocorticoid hormone action during the cell cycle. Work in this and other laboratories has established that the progression of cells through the cell cycle results in significant alterations in glucocorticoid receptor number and structure. We will now focus our studies on the regulation of the glucocorticoid receptor gene during the cell cycle. The availability of cDNA clones of the human glucocorticoid receptor permits us to extend our analysis of receptor regulation to the molecular level. We hypothesize that changes in cellular glucocorticoid receptor number during the cell cycle can be accounted for by alteration in receptor gene regulation. To address this question we will evaluate glucocorticoid receptor mRNA accumulation, transcription and stability during the cell cycle. Concurrently the organizational structure of the glucocorticoid receptor gene will be assessed to determine what relationship, if any, exists between receptor gene transcription and receptor gene structure. Further studies will also be initiated to identify and characterize the DNA sequences necessary for glucocorticoid receptor gene expression. Finally we seek to evaluate further a recent observation made in our laboratory which demonstrates the interaction of the human glucocorticoid receptors with the coding domain of its gene. Specifically we will characterize by several criteria the interactions between glucocorticoid receptor and its own gene and evaluate in vivo the physiological significance of such interactions. Together the studies proposed in the application should lead to a better understanding of the mechanisms involved in the regulation of human glucocorticoid receptor gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032460-08
Application #
3230873
Study Section
Endocrinology Study Section (END)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Gowda, B; Sar, M; Mu, X et al. (1996) Coordinate modulation of glucocorticoid receptor and glutaminase gene expression in LLC-PK1-F+ cells. Am J Physiol 270:C825-31
Evans-Storms, R B; Cidlowski, J A (1995) Regulation of apoptosis by steroid hormones. J Steroid Biochem Mol Biol 53:1-8
Webster, J C; Cidlowski, J A (1994) Downregulation of the glucocorticoid receptor. A mechanism for physiological adaptation to hormones. Ann N Y Acad Sci 746:216-20
Silva, C M; Powell-Oliver, F E; Jewell, C M et al. (1994) Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid. Steroids 59:436-42
Burnstein, K L; Jewell, C M; Sar, M et al. (1994) Intragenic sequences of the human glucocorticoid receptor complementary DNA mediate hormone-inducible receptor messenger RNA down-regulation through multiple mechanisms. Mol Endocrinol 8:1764-73
Oakley, R H; Cidlowski, J A (1993) Homologous down regulation of the glucocorticoid receptor: the molecular machinery. Crit Rev Eukaryot Gene Expr 3:63-88
Tully, D B; Cidlowski, J A (1993) Protein-blotting procedures to evaluate interactions of steroid receptors with DNA. Methods Enzymol 218:535-51
Silva, C M; Cidlowski, J A (1992) The effect of oxidation/reduction on the charge heterogeneity of the human glucocorticoid receptor. J Steroid Biochem Mol Biol 41:1-10
Bellingham, D L; Sar, M; Cidlowski, J A (1992) Methotrexate-induced overexpression of functional glucocorticoid receptors in Chinese hamster ovary cells. Mol Cell Endocrinol 83:153-71
Bellingham, D L; Sar, M; Cidlowski, J A (1992) Ligand-dependent down-regulation of stably transfected human glucocorticoid receptors is associated with the loss of functional glucocorticoid responsiveness. Mol Endocrinol 6:2090-102

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