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Trans-activation by thyroid hormone receptors: functional parallels with steroid hormone receptors
1Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92138.
Abstract:
The effects of thyroid hormones are mediated through nuclear receptor proteins that modulate the transcription of specific genes in target cells. We previously isolated cDNAs encoding two different mammalian thyroid hormone receptors, one from human placenta (hTR beta) and the other from rat brain (rTR alpha), and showed that their in vitro translation products bind thyroid hormones with the characteritistic affinities of the native thyroid hormone receptor. We now demonstrate that both of the cloned receptors activate transcription from a thyroid hormone-responsive promoter in a hormone-dependent manner, with rTR alpha eliciting a greater response than hTR beta. The putative functional domains of the thyroid hormone receptors were examined by creating chimeric thyroid hormone/glucocorticoid receptors, producing receptors with hybrid functional properties. These experiments support the proposal that the thyroid hormone receptors are composed of interchangeable functional domains, and indicate that the mechanism of hormone-inducible gene regulation has been conserved in steroid and thyroid hormone receptors.
Insights
Researchers identified two thyroid hormone receptors (TRs) that activate gene transcription. Chimeric receptors revealed interchangeable functional domains, suggesting conserved gene regulation mechanisms between thyroid and steroid hormone receptors.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Nuclear Receptors
Background:
- Thyroid hormones regulate gene transcription via nuclear receptor proteins.
- Two distinct mammalian thyroid hormone receptors, hTR beta and rTR alpha, were previously isolated.
- These receptors bind thyroid hormones with native receptor affinities.
Purpose of the Study:
- To demonstrate the transcriptional activity of cloned thyroid hormone receptors.
- To investigate the functional domains of thyroid hormone receptors.
- To explore conserved mechanisms in hormone-inducible gene regulation.
Main Methods:
- In vitro translation of cloned cDNAs for hTR beta and rTR alpha.
- Assaying hormone-dependent transcriptional activation from a thyroid hormone-responsive promoter.
- Construction and analysis of chimeric thyroid hormone/glucocorticoid receptors.
Main Results:
- Both hTR beta and rTR alpha activated transcription in a hormone-dependent manner.
- rTR alpha showed a greater transcriptional response compared to hTR beta.
- Chimeric receptors exhibited hybrid functional properties, indicating interchangeable domains.
Conclusions:
- Thyroid hormone receptors modulate gene transcription.
- Thyroid hormone receptors possess interchangeable functional domains.
- Mechanisms of hormone-inducible gene regulation are conserved across steroid and thyroid hormone receptors.