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Activation and repression by nuclear hormone receptors: hormone modulates an equilibrium between active and
I G Schulman1, H Juguilon, R M Evans
1Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Abstract:
Transactivation-defective retinoid X and thyroid hormone receptors have been used to examine mechanisms of hormonal activation. Activation and repression of transcription by retinoid X and thyroid hormone receptors are shown to be mediated by physically distinct and functionally independent regions of the hormone binding domain. Nevertheless, the ability of receptors to respond to hormone requires communication between both functional domains. Deletion of the hormone-dependent transactivation function of the retinoid X receptor, the common subunit of heterodimeric nuclear receptors, significantly impairs hormone-dependent transcription by retinoic acid, thyroid hormone, and vitamin D receptors. The results indicate that receptors do not exist in static off and on conformations but that hormone alters an equilibrium between inactive and active states.
Insights
Hormone receptors like retinoid X and thyroid hormone receptors shift between inactive and active states upon hormone binding. This dynamic equilibrium, rather than static conformations, governs transcriptional regulation.
Area of Science:
- Molecular Biology
- Endocrinology
- Genetics
Background:
- Nuclear receptors, including retinoid X and thyroid hormone receptors, regulate gene expression in response to hormones.
- Understanding the precise mechanisms of hormonal activation and repression is crucial for deciphering cellular signaling pathways.
Purpose of the Study:
- To investigate the functional domains responsible for transcriptional activation and repression by retinoid X and thyroid hormone receptors.
- To elucidate the role of communication between receptor domains in mediating hormonal responses.
Main Methods:
- Utilizing transactivation-defective retinoid X and thyroid hormone receptors to dissect functional domains.
- Employing genetic manipulation, including deletion of specific functional regions, to assess their impact on transcription.
Main Results:
- Activation and repression are mediated by distinct, independent regions within the hormone-binding domain.
- Communication between these domains is essential for receptor response to hormones.
- Disrupting the retinoid X receptor's transactivation function impairs hormone-dependent transcription across multiple nuclear receptor systems.
Conclusions:
- Hormonal activation involves a dynamic equilibrium shift between inactive and active receptor states, not static conformational changes.
- Nuclear receptor function relies on intricate communication between physically separate functional domains.
- The retinoid X receptor plays a critical role as a common subunit in mediating hormonal responses for various nuclear receptors.