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Updated: Aug 13, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Lives and times of nuclear receptors
1Department of Physiology, University of Wisconsin-Madison, 120 Service Memorial Institute, 1300 University Avenue, Madison, Wisconsin 53706, USA. alarid@physiology.wisc.edu
Abstract:
Down-regulation of receptor in response to ligand was one of the earliest functional readouts of steroid hormone action. The loss of total receptor content upon stimulation, referred to initially as receptor "processing," was carefully described with respect to receptor nuclear transformation or tight nuclear binding. It was these early studies that were the first to note a correlation between receptor turnover and induction of gene transcription, leading to the proposal that down-regulation of receptor was involved in mechanisms of transcriptional activation. This idea has now attracted renewed attention with the discovery that ligand-induced "processing" in the form of proteolysis is carried out by the 26S proteasome, a multicatalytic enzyme whose activity is directly coupled to cell-cycle control, signal transduction, and importantly, transcription. Here, we review our current understanding of the mechanism and relevance of proteolysis to receptor function based on general concepts that have emerged from analyses of liganded members of the nuclear receptor family.
Insights
Ligand-induced receptor down-regulation, initially termed processing, involves proteolysis by the 26S proteasome. This mechanism is crucial for transcriptional activation and nuclear receptor function.
Area of Science:
- Molecular Biology
- Endocrinology
- Biochemistry
Background:
- Steroid hormone action was early characterized by ligand-induced receptor down-regulation, termed processing.
- Early studies noted a correlation between receptor turnover and gene transcription induction.
Purpose of the Study:
- To review the mechanism and relevance of proteolysis in nuclear receptor function.
- To explore the link between ligand-induced receptor processing and transcriptional activation.
Main Methods:
- Review of existing literature on nuclear receptor family analyses.
- Examination of the role of the 26S proteasome in receptor processing.
Main Results:
- Ligand-induced receptor processing involves proteolysis mediated by the 26S proteasome.
- The 26S proteasome's activity is linked to cell-cycle control, signal transduction, and transcription.
Conclusions:
- Proteolysis is a key mechanism in nuclear receptor function and transcriptional regulation.
- Understanding proteolysis offers renewed insight into steroid hormone action and gene transcription.
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