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Published on: September 25, 2017
Subcellular localization modulates activation function 1 domain phosphorylation in the androgen receptor.
Cristina T Kesler1, Daniel Gioeli, Mark R Conaway
1Center for Cell Signaling, Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Molecular Endocrinology (Baltimore, Md.)
|June 21, 2007
Summary
Androgen receptor (AR) shuttling between the nucleus and cytoplasm is crucial for regulating gene transcription. Transient nuclear presence of AR is sufficient for transcriptional activity, influenced by phosphorylation.
Area of Science:
- Molecular Biology
- Cell Biology
- Endocrinology
Background:
- The androgen receptor (AR) is primarily nuclear in cells treated with androgens, but it also shuttles between the nucleus and cytoplasm.
- Understanding the role of this nucleocytoplasmic shuttling is key to comprehending AR regulation.
Purpose of the Study:
- To investigate how nucleocytoplasmic shuttling regulates androgen receptor (AR) function.
- To determine the effects of forced nuclear or cytoplasmic localization on AR activity.
Main Methods:
- Engineered AR with nuclear localization signals (NLS) or nuclear export signals (NES) to control its cellular compartment.
- Assessed AR's transcriptional activity on reporter genes (PSA, MMTV) and endogenous genes.
- Analyzed androgen binding kinetics and AR phosphorylation status using phosphosite-specific antibodies.
Main Results:
- Forced nuclear AR exhibited transcriptional activity, while forced cytoplasmic AR showed surprising activity on certain promoters, indicating transient nuclear localization is sufficient for transcription.
- Androgen binding affinity (K(D)) and dissociation rates were unaffected by AR compartmentalization.
- AR compartmentalization influenced phosphorylation patterns, with specific sites phosphorylated in a compartment-dependent manner.
Conclusions:
- Nucleocytoplasmic shuttling of AR integrates cytoplasmic signaling cues with nuclear transcriptional activity.
- Compartmentalization impacts AR phosphorylation, suggesting a mechanism for modulating AR function.
- Transient nuclear AR localization is sufficient for transcriptional activation, highlighting the dynamic nature of AR regulation.
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