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.
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