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Submitted on April 17, 2003
Accepted on November 26, 2003
1 Center for Cell Signaling, Department of Biochemistry and Molecular Genetics, Cell and Molecular Biology Program, and Department of Microbiology, Department of Health Evaluation Sciences; University of Virginia, Charlottesville, VA 22908
* To whom correspondence should be addressed. E-mail: paschal{at}virginia.edu.
Here we report that mutations within the DNA-binding domain of AR, shown previously to inhibit nuclear export to the cytoplasm, cause an androgen-dependent defect in intra-nuclear trafficking of AR. Mutation of two conserved phenylalanines within the DNA recognition helix (F582,583A) results in androgen-dependent arrest of AR in multiple sub-nuclear foci. A point mutation in one of the conserved phenylalanines (
F582,F582Y) is known to cause Androgen Insensitivity Syndrome (AIS). Both AIS mutants (F582,F582Y) and the export mutant (F582,583A) displayed androgen-dependent arrest in foci, and all three mutants promoted androgen-dependent accumulation of the histone acetyl transferase CBP in the foci. The foci correspond to a sub-nuclear compartment that is highly enriched for the steroid receptor co-activator GRIP-1. Agonist-bound WT AR induces the redistribution of GRIP-1 from foci to the nucleoplasm. This likely reflects a direct interaction between these proteins because mutation of a conserved residue within the major co-activator binding site on AR (K720A) inhibits AR-dependent dissociation of GRIP-1 from foci. GRIP-1 also remains foci-associated in the presence of agonist-bound F582,583A, F582, or F582Y forms of AR. Two-dimensional phospho-peptide mapping and analysis with a phospho-specific antibody revealed that mutant forms of AR that arrest in the sub-nuclear foci are hypo-phosphorylated at Ser81, a site that normally undergoes androgen-dependent phosphorylation. Our working model is that the sub-nuclear foci are sites where AR undergoes ligand-dependent engagement with GRIP-1 and CBP, a recruitment step that occurs before Ser81 phosphorylation and association with promoters of target genes.
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