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Characterization of Nuclear Import of the Domain-Specific Androgen Receptor in Association with the Importin /β and Ran-Guanosine 5'-Triphosphate Systems

Departments of Anatomy and Neurobiology (N.K., K.-i.M., M.K.) and Biochemistry and Molecular Genetics (A.T.), Research Institute for Geriatric and Neurobiological Diseases, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

Address all correspondence and requests for reprints to: Mitsuhiro Kawata, M.D., Ph.D., Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: mkawata{at}koto.kpu-m.ac.jp.

Androgen induces androgen receptor (AR) nuclear import, which allows AR to act as a transcriptional factor and ultimately leads to biological activity. However, the mechanism of AR translocation to the nucleus is still unclear. In the present study, we assessed the nuclear import abilities of each domain of AR and their mechanisms related to Ran and importin /β using green fluorescent protein real-time imaging. The localization of AR to the nucleus in the absence and presence of ligands was dependent upon a complex interplay of the amino terminal transactivation domain (NTD), the DNA binding domain (DBD), and the ligand binding domain (LBD). NTD and DBD showed ligand-independent nuclear import ability, whereas LBD had ligand-dependent transport. In addition, AR deletion mutant lacking DBD was distributed in the cytoplasm regardless of ligand existence, suggesting that the remaining domains, NTD and LBD, are responsible for AR cytoplasmic localization. Cotransfection with a dominant negative form of Ran dramatically inhibited the nuclear import of all AR domains, and a dominant negative form of importin prevented AR and DBD import. Importin β-knockdown strongly blocked DBD import. These results indicate that there are two additional nuclear localization signals (NLSs) in the NTD and LBD, and there are distinct pathways used to attain domain-specific AR nuclear import: the NLS of DBD is Ran and importin /β-dependent, whereas the NLSs of NTD and LBD are Ran dependent but importin /β-independent. Our data suggest that the nuclear import of AR is regulated by the interplay between each domain of the AR.