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Transcriptional repression by nuclear receptors: mechanisms and role in disease
1MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, U.K. and Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K.
Abstract:
Co-repressor proteins mediate transcriptional repression by nuclear receptors in the absence of ligand. The identification of a co-repressor-receptor interaction motif, and the finding that co-repressors and co-activators compete for the same site on the receptor, suggests a simple mechanism for the switch from repression to activation upon ligand binding. Defects in this mechanism result in dominant-negative receptors that repress transcription. Such receptors have been implicated in several clinically important diseases, including thyroid hormone resistance and diabetes mellitus.
Insights
Co-repressor proteins silence gene transcription by nuclear receptors without a ligand. Ligand binding triggers a switch to activation, and defects cause disease, impacting thyroid hormone resistance and diabetes mellitus.
Area of Science:
- Molecular Biology
- Genetics
- Endocrinology
Background:
- Nuclear receptors regulate gene expression.
- Co-repressor proteins are essential for transcriptional repression in the absence of ligands.
- The interplay between co-repressors and co-activators dictates transcriptional outcomes.
Purpose of the Study:
- To elucidate the mechanism by which co-repressors mediate transcriptional repression by nuclear receptors.
- To understand the role of ligand binding in switching nuclear receptor activity from repression to activation.
- To investigate the consequences of defects in this regulatory mechanism.
Main Methods:
- Identification of a co-repressor-receptor interaction motif.
- Analysis of co-repressor and co-activator competition for nuclear receptor binding sites.
Main Results:
- A specific co-repressor-receptor interaction motif was identified.
- Co-repressors and co-activators compete for the same binding site on nuclear receptors.
- This competition provides a mechanism for ligand-induced switching from repression to activation.
Conclusions:
- The findings suggest a simple mechanism for regulating nuclear receptor activity.
- Defects in this mechanism lead to dominant-negative receptors.
- These dominant-negative receptors are implicated in diseases like thyroid hormone resistance and diabetes mellitus.