GLUCOCORTICOID ACTION IN SYNCHRONIZED CELLS

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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.