Activation (or transformation) is the process by which the glucocorticoid- receptor complex is converted from a non-DNA binding protein to one that is capable of binding to DNA. This process appears to be highly regulated and occurs both in vitro and in vivo. The present proposal is concerned with one regulator of activation called modulator. Modulator is commonly known as the low-molecular weight heat-stable inhibitor of glucocorticoid- receptor complex activation. We recently reported the complete purification and initial characterization of modulator from rat liver. Purified modulator inhibits glucocorticoid-receptor complex activation and stabilizes the steroid binding ability of the unoccupied glucocorticoid receptor. Since these biological properties are shared by exogenous sodium molybdate, modulator appears to be the endogenous factor that exogenous sodium molybdate mimics. Structural analysis of purified modulator indicates that modulator is a novel ether aminophosphoglyceride. From these functional and structural studies, we postulate that modulator acts by cross-linking the subunits of the unoccupied/unactivated glucocorticoid receptor. In this proposal, we cite four specific aims concerning modulator: 1. Determination of the mechanism of action of modulator with the purified glucocorticoid receptor; 2. Analysis of the activity of modulator in cells in culture; 3. Measurement of the effects of modulator on other steroid hormone receptors; 4. Production and characterization of an antibody to modulator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042353-04
Application #
3243418
Study Section
Endocrinology Study Section (END)
Project Start
1991-07-01
Project End
1993-08-31
Budget Start
1992-01-01
Budget End
1993-08-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Robertson, N M; Bodine, P V; Hsu, T C et al. (1995) Modulator inhibits nuclear translocation of the glucocorticoid receptor and inhibits glucocorticoid-induced apoptosis in the human leukemic cell line CEM C-7. Cancer Res 55:548-56
Bodine, P V; Alnemri, E S; Litwack, G (1995) Synthetic peptides derived from the steroid binding domain block modulator and molybdate action toward the rat glucocorticoid receptor. Receptor 5:117-22
Bodine, P V; Hajdu, J; Litwack, G (1994) A new synthetic ether aminophosphoglyceride exhibits partial modulator activity towards the glucocorticoid receptor. Biochem Biophys Res Commun 203:408-15
Celiker, M Y; Haas, A; Saunders, D et al. (1993) Specific regulation of male rat liver cytosolic estrogen receptor by the modulator of the glucocorticoid receptor. Biochem Biophys Res Commun 195:151-7
Schulman, G; Bodine, P V; Litwack, G (1992) Modulators of the glucocorticoid receptor also regulate mineralocorticoid receptor function. Biochemistry 31:1734-41
Maksymowych, A B; Hsu, T C; Litwack, G (1992) A novel, highly conserved structural motif is present in all members of the steroid receptor superfamily. Receptor 2:225-40
Hsu, T C; Bodine, P V; Litwack, G (1991) Endogenous modulators of glucocorticoid receptor function also regulate purified protein kinase C. J Biol Chem 266:17573-9
Bodine, P V; Garcia, M L; Pascual, J et al. (1991) Evaluation of synthetic novel ether aminophosphoglycerides for glucocorticoid-receptor complex modulator activity. Receptor 1:167-80
Bodine, P V; Litwack, G (1990) Purification and characterization of two novel phosphoglycerides that modulate the glucocorticoid-receptor complex. Evidence for two modulator binding sites in the occupied/unactivated steroid hormone receptor. J Biol Chem 265:9544-54
Bodine, P V; Litwack, G (1990) Modulator: the missing link. Mol Cell Endocrinol 74:C77-81

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