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Mechanisms of androgen receptor activation and function
A O Brinkmann1, L J Blok, P E de Ruiter
1Department of Endocrinology & Reproduction, Erasmus University Rotterdam, The Netherlands. brinkmann@endov.fgg.eur.nl
Abstract:
Androgens play a crucial role in several stages of male development and in the maintenance of the male phenotype. Androgens act in their target cells via an interaction with the androgen receptor, resulting in direct regulation of gene expression. The androgen receptor is a phosphoprotein and modulation of the phosphorylation status of the receptor influences ligand-binding and consequently transcription activation of androgen responsive genes. Androgen binding induces a conformational change in the ligand-binding domain, accompanied by additional receptor phosphorylation. Subsequently the liganded androgen receptor interacts with specific androgen response elements in the regulatory regions of androgen target genes, resulting in stimulation of gene expression. Anti-androgens induce a different conformational change of the ligand-binding domain, which does not or only partially result in stimulation of transactivation. Interestingly, different anti-androgens can induce different inactive conformations of the androgen receptor ligand-binding domain. Recent evidence strongly supports a ligand dependent functional interaction between the ligand-binding domain and the NH2-terminal transactivating domain of the androgen receptor. Two regions in the NH2-terminal domain are involved in this interaction, whereas in the ligand-binding domain the AF-2 AD core region is involved.
Insights
Androgen receptor (AR) phosphorylation affects its ability to regulate gene expression. Different anti-androgens induce distinct inactive AR conformations, impacting male development and phenotype maintenance.
Area of Science:
- Molecular Endocrinology
- Cellular Biology
- Genetics
Background:
- Androgens are vital for male development and maintaining the male phenotype.
- Androgen action relies on the androgen receptor (AR), a phosphoprotein that regulates gene expression.
- AR phosphorylation status critically influences ligand binding and transcriptional activity.
Purpose of the Study:
- To elucidate the role of androgen receptor phosphorylation in gene regulation.
- To investigate the conformational changes induced by androgens and anti-androgens.
- To identify the interaction domains within the AR involved in ligand-dependent transactivation.
Main Methods:
- Analysis of androgen receptor phosphorylation.
- Conformational analysis of the ligand-binding domain upon androgen and anti-androgen binding.
- Investigation of functional interactions between AR domains.
Main Results:
- Androgen binding induces conformational changes and additional AR phosphorylation, leading to gene expression.
- Anti-androgens induce distinct inactive AR conformations, with varying effects on transactivation.
- A ligand-dependent interaction between the AR's ligand-binding domain and NH2-terminal domain was confirmed.
Conclusions:
- AR phosphorylation is a key modulator of androgen-responsive gene expression.
- The specific conformation of the AR, dictated by ligand binding, determines its transcriptional activity.
- Understanding these interactions is crucial for comprehending androgen action and developing targeted therapies.