Molecular mechanisms of glucocorticoid hormone action

Abstract

In the current studies, several aspects of glucocorticoid action have been investigated. The data provide further evidence for the notion that under physiological conditions the glucocorticoid-receptor interaction in the intact cell is driven primarily by hydrophobic interactions and that the initial steroid-receptor interaction rather than transport process or subsequent hormone-induced conformational changes in the receptor-steroid complex associated with activation or chromatin binding of the complexes is the limiting determinant for the overall steroid-binding reaction in the intact cell. Agonists require longer to bind to receptors than the antagonist progesterone and remain bound longer than the antagonist; this may reflect either agonist-induced conformational changes associated with the initial agonist-receptor reaction that are not induced by the antagonist or else a requirement for a more prolonged receptor residency time for agonist actions. The receptor is a single polypeptide chain of 87 000 molecular weight and a domain of it required for receptor action is probably on the carboxy-terminal portion of the molecule and is distinct from the steroid- and DNA-binding domains. The receptor-glucocorticoid complex binds to chromatin acceptor sites that involve DNA and other chromatin functions (probably proteins) and that are in excess over the receptor. These interactions lead to changes in chromatin structure that may reflect the primary receptor effect. The chromatin interactions can then lead to an increase in the number of RNA polymerase molecules engaged in transcribing a glucocorticoid-regulated gene (growth hormone). This can lead to an increase in pre-mRNA and consequently the mRNA product of the gene.