Molecular Mechanisms of Glucocorticoid Hormone Action

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DESCRIPTION (provided by applicant): Understanding the mechanisms of regulation of gene expression is essential to a comprehension of development and differentiation, and thus, cancer and other disorders that may arise when these processes go awry. Glucocorticoids and progestins regulate numerous processes in normal physiology and disease including pregnancy, lung and breast development, stress response, inflammation, and cancer. The receptors for these steroid hormones control these processes by regulation transcription of target genes. Our long term goal is to understand the molecular details of these regulatory mechanisms. Such knowledge could drive the improvement of existing therapeutic regimens and the development of novel avenues for intervention, particularly in endocrine-dependent neoplasia and inflammatory disease. This application addresses two very broad and fundamental issues in the regulation of gene expression. The first is the role of chromatin in gene expression and the second is how two transcription factors that have little ability to distinguish individual DNA target sites can mediate very different biological actions. The focus of the first aim is to apply new strategies we have developed or brought to the lab to maintain the recycling of glucocorticoid receptor activity in the context of an in vitro transcription system. A key feature of this system is that it employs chromatin templates in order to understand mechanisms of receptor action in a more biologically relevant context. The second aim builds on the first to examine the role of individual coregulatory proteins in glucocorticoid receptor action in vitro. The role of chromatin remodeling and modification will be a special focus. The third and fourth aims are directed toward understanding mechanisms of differential gene regulation by glucocorticoid and progesterone receptors. We will exploit differentially expressed genes we have recently identified in aim three for mechanistic studies. In aim four we will expand on our novel finding that the chromatin environment surrounding a promoter can influence gene regulation by receptors in both a qualitative and quantitative fashion by identifying additional examples and analyzing the chromosomal sites to understand the basis of this regulation. Together these studies will make significant contributions to our understanding of hormone action.