Identification and characterization of a ligand-regulated nuclear export signal in androgen receptor.
Androgen receptor (AR) belongs to the steroid receptor superfamily that regulates gene expression in a ligand-dependent fashion. AR is localized to the cytoplasm in the absence of androgen and translocates into the nuclei to activate gene expression in the presence of ligand. Regulation of AR nuclear import and export represents an essential step in androgen action. A nuclear localization signal (NLS) has been identified in the DNA-binding domain and hinge region of AR and other steroid receptors. Studies on nuclear export of AR, however, are limited, and what might be the underlying mechanism regulating the intracellular localization of steroid receptors is unclear. Our studies have identified a leptomycin B-insensitive nuclear export signal (NESAR) in the ligand-binding domain of AR, which is active in the absence of androgen and repressed upon ligand binding. Consistent with its androgen-sensitivity, NESAR contains amino acid residues in the immediate vicinity of the bound ligand. NESAR is necessary for AR nuclear export and is dominant over the NLS in the DNA-binding domain and hinge region in the absence of hormone. Our findings suggest that androgen can regulate NESAR and, subsequently, the NLS of the AR, providing a mechanism by which androgen regulates AR nuclear/cytoplasmic shuttling. Estrogen receptor alpha and mineralocorticoid receptor also contain functional NES, suggesting that this ligand-regulated NES is conserved among steroid receptors.
Saporita
Anthony J
AJ
Department of Urology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
Zhang
Qiuheng
Q
Navai
Neema
N
Dincer
Zehra
Z
Hahn
Junghyun
J
Cai
Xiaoyan
X
Wang
Zhou
Z
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000595:Amino Acid Sequence; D000728:Androgens / Q000494:pharmacology; D001665:Binding Sites; D017124:Conserved Sequence; D047628:Estrogen Receptor alpha; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010449:Peptide Mapping; D021382:Protein Sorting Signals / Q000235:genetics; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry; D018161:Receptors, Mineralocorticoid / Q000737:chemistry; D017384:Sequence Deletion
D000728:Androgens; D047628:Estrogen Receptor alpha; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D021382:Protein Sorting Signals; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D018161:Receptors, Mineralocorticoid; C038753:leptomycin B