Mechanisms of glucocorticoid hormone action

Nancy C. Lan, Michael Karin, Thai Nguyen, Alessandro Weisz, Morris J. Birnbaum, Norman L. Eberhardt, John D. Baxter

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Abstract

This work summarizes some of our studies of the mechanisms of glucocorticoid action, including aspects of steroid binding to receptors, the activation of glucocorticoid-receptor complexes and the regulation of expression of endogenous and transferred glucocorticoid-responsive genes. Studies of the receptor-steroid interaction support the notion that steroid entry is passive. A comparative analysis of binding in isolated cytosol and intact cells suggests that the initial receptor-steroid binding reaction and not subsequent steps such as activation and nuclear binding, is predominantly responsible for the high-affinity state that is generated. The binding is driven by entropy and enthalpy changes at low temperature; at higher temperatures it is driven by entropy changes, with enthalpy working against it. Studies of the activation of the receptor-glucocorticoid complex with the use of highly purified receptors suggest that this step is associated with a change in charge of the receptor-glucocorticoid complex (such as would occur with a dephosphorylation reaction), whereas the data do not support the notion that dissociation of a bound RNA or of receptor oligomers is responsible for generating the nuclear- and DNA-binding activity of the complex. Studies of the regulation by glucocorticoids of expression of the endogenous rat growth hormone (rGH) gene in cultured rat pituitary tumor (GC, GH3D6) cells suggest that glucocorticoids increase the expression of this gene by multiple mechanisms. First, there is a modest direct stimulation of transcription by a mechanism(s) that does not depend on protein synthesis; however, if the cells have been exposed to thyroid hormone for several hours, the steroid exerts a much greater increase in rGH pre-mRNA levels. Secondly, the steroid appears to stimulate some relatively stable function or functions that increase the ability of thyroid hormone to increase rGH levels. Thirdly, the steroid probably increases rGH mRNA stability, since the fold-increases in rGH mRNA exceed those of transcription. Finally, the steroid may, by unknown mechanisms, affect rGH mRNA polyadenylation. The gene transfer experiments utilized the rat and human (h) GH genes and hybrid genes containing either rGH and Herpes Simplex virus thymidine kinase (TK) gene sequences or the human metallothionein-IIA (hMT-IIA) and TK gene sequences. The steroid was found to regulate hMT-IIA gene expression in all glucocorticoid-responsive cell types tested by actions on its 5'-flanking DNA. By contrast, the glucocorticoid regulated GH gene expression in some but not all glucocorticoid-responsive cell types. These data suggest that factors in addition to glucocorticoid receptors are necessary for the steroid to regulate GH gene expression. The use of hybrid hMT-IIA-TK genes indicated that glucocorticoids act on the hMT-IIA gene upstream from and independently of its "TATA" box to increase promoter activity. The steroid can affect multiple promoters simultaneously, even those of heterologous genes, and can affect these at a distance of at least 600 nucleotides away by a mechanism that resembles somewhat the actions of enhancer sequences described for other genes. Because of these findings and our earlier observations that glucocorticoids can modify chromatin structure in a way that is preserved in isolated nuclei, a model is presented whereby the glucocorticoid-receptor complex binding to chromatin modifies chromatin structure to make it more available over a considerable segment of DNA for RNA polymerase entry.

Original languageEnglish (US)
Pages (from-to)77-88
Number of pages12
JournalJournal of Steroid Biochemistry
Volume20
Issue number1
DOIs
StatePublished - 1984
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

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    Lan, N. C., Karin, M., Nguyen, T., Weisz, A., Birnbaum, M. J., Eberhardt, N. L., & Baxter, J. D. (1984). Mechanisms of glucocorticoid hormone action. Journal of Steroid Biochemistry, 20(1), 77-88. https://doi.org/10.1016/0022-4731(84)90192-4