Regulation of progesterone receptor expression and activity in uterine cells: Analysis of the molecular actions of estrogens and progestins on the progesterone receptor gene
Kraus, William Lee
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Permalink
https://hdl.handle.net/2142/19987
Description
Title
Regulation of progesterone receptor expression and activity in uterine cells: Analysis of the molecular actions of estrogens and progestins on the progesterone receptor gene
Author(s)
Kraus, William Lee
Issue Date
1994
Doctoral Committee Chair(s)
Katzenellenbogen, Benita S.
Department of Study
Molecular and Integrative Physiology
Discipline
Molecular and Integrative Physiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Biology, Animal Physiology
Language
eng
Abstract
Estrogens and progestins play important roles in many aspects of female reproductive biology. These hormones exert their effects via intracellular protein receptors, termed estrogen receptors (ERs) and progestin receptors (PRs). We have examined the regulation of PR levels in the rat uterus by estrogens and progestins, as well as the molecular mechanisms through which these hormones act. Our studies have shown that estradiol $\rm (E\sb2)$ causes rapid time- and dose-dependent increases in uterine PR mRNA and protein when administered to immature rats in vivo. These $\rm E\sb2$-mediated effects were reduced by cotreatment with progesterone or antiestrogen. To better define the molecular mechanisms controlling the $\rm E\sb2$-mediated effects, we cloned and characterized the $5\sp\prime$-region of the rat PR gene, including two functionally distinct promoters which were stimulated differently by $\rm E\sb2$, as well as by cyclic AMP (cAMP) through an ER-dependent mechanism. In subsequent studies, we identified and characterized a complex estrogen-responsive unit (ERU) in the rat PR gene, comprised of at least five different regions of the gene. The organization of the ERU was unique and defined a novel paradigm for the composition of a steroid hormone-responsive unit (SRU). Finally, we examined the ability of ligand-occupied PR to repress ER-mediated transcriptional activity at the gene level as a possible mechanism by which progesterone inhibits $\rm E\sb2$ stimulation of the rat PR gene. In our studies, the repression was demonstrable, and the magnitude of the repression varied depending on the PR isoform, PR levels, ligand type (i.e. agonist or antagonist), ligand concentration, promoter context and cell type, as well as the composition of the SRU. Together, these studies have helped to elucidate some of the molecular mechanisms mediating regulation of PR gene expression in rat uterine tissue by estrogen, progesterone and cAMP.
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