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A thyroid hormone receptor-dependent glucocorticoid induction
J Leers1, C Steiner, R Renkawitz
1Genetisches Institut, Justus-Liebig-Universität, Giessen, Germany.
Abstract:
Glucocorticoid and thyroid hormones exert their effects in many body tissues by binding to their respective receptors. The search for possible cross-talking mechanisms in overlapping target cells led to the discovery of synergism between a thyroid hormone receptor-binding site and a cryptic glucocorticoid-responsive element. Glucocorticoid responsiveness could only be detected in the presence of thyroid hormone and its receptor. This synergism requires the glucocorticoid receptor (GR) DNA-binding domain and is mediated by the transactivation domains. We found that synergism also occurs when the thyroid hormone receptor is replaced by the retinoic acid receptor or the GR is replaced by the progesterone receptor. Synergism is qualitatively independent of the type of thyroid hormone receptor-binding site and promoter. In several combinations of promoter and response elements, including a retinoic acid response element, T3 induction was only seen in the presence of the cryptic glucocorticoid-responsive element, GR, and glucocorticoids.
Insights
Glucocorticoid and thyroid hormone receptors show synergistic effects, with glucocorticoid responsiveness dependent on thyroid hormone presence. This interaction involves specific receptor domains and is observed across different hormone receptor types.
Area of Science:
- Endocrinology
- Molecular Biology
- Cellular Biology
Background:
- Glucocorticoid and thyroid hormones regulate gene expression via specific receptors.
- Understanding cross-talk between these hormonal pathways is crucial for elucidating complex cellular responses.
Purpose of the Study:
- To investigate potential cross-talking mechanisms between thyroid hormone and glucocorticoid signaling pathways.
- To identify conditions and molecular components required for observed synergistic effects.
Main Methods:
- Utilized reporter gene assays to measure transcriptional activity.
- Employed various combinations of hormone response elements, receptor types, and ligands.
- Investigated the roles of specific receptor domains (DNA-binding, transactivation) in mediating synergism.
Main Results:
- Discovered a synergistic interaction between thyroid hormone receptor-binding sites and cryptic glucocorticoid-responsive elements.
- Glucocorticoid responsiveness was contingent upon the presence of thyroid hormone and its receptor.
- Synergism was dependent on the glucocorticoid receptor's DNA-binding domain and transactivation domains.
- Observed similar synergistic effects when substituting thyroid hormone receptors with retinoic acid receptors or glucocorticoid receptors with progesterone receptors.
- Demonstrated that this synergism is largely independent of the specific thyroid hormone receptor-binding site and promoter used.
- Identified instances where thyroid hormone induction (T3) required the presence of the glucocorticoid-responsive element, glucocorticoid receptor, and glucocorticoids.
Conclusions:
- A novel form of hormone receptor cross-talk, termed synergism, exists between glucocorticoid and thyroid hormone signaling pathways.
- This synergism is mediated by specific interactions involving the glucocorticoid receptor's DNA-binding and transactivation domains.
- The findings highlight the intricate regulatory networks governing nuclear receptor function and gene expression.