This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawate, H. Articles by Takayanagi, R. Search for Related Content PubMed PubMed Citation Articles by Kawate, H. Articles by Takayanagi, R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Genetics Home Reference Related Collections Male Endocrinology

Impaired Nuclear Translocation, Nuclear Matrix Targeting, and Intranuclear Mobility of Mutant Androgen Receptors Carrying Amino Acid Substitutions in the Deoxyribonucleic Acid-Binding Domain Derived from Androgen Insensitivity Syndrome Patients

Departments of Geriatric Medicine (H.K., Y.W., K.O., R.-H.T., R.T.) and Medicine and Bioregulatory Science (T.O., T.Y., H.N.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of the Second Anatomy (K.N.), Kurume University School of Medicine, Kurume, 830-0011, Japan

Address all correspondence and requests for reprints to: Ryoichi Takayanagi, Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: takayana{at}geriat.med.kyushu-u.ac.jp.

Context: Recent imaging studies revealed that androgen receptor (AR) is ligand-dependently translocated from the cytoplasm into the nucleus and forms intranuclear fine foci. In this study, we examined whether intracellular dynamics of mutant ARs detected in two androgen insensitivity syndrome (AIS) patients was impaired.

Objective: ARs with mutations in the DNA-binding domain were functionally characterized and compared with the wild-type AR.

Patients: In a complete AIS patient (subject 1), cysteine residue 579 in the first zinc finger motif of AR was substituted for phenylalanine (AR-C579F). Another mutation (AR-F582Y) was found in a partial AIS patient (subject 2).

Results: AR-F582Y retained less than 10% of the transactivation activity of the wild-type AR, whereas no ligand-dependent transactivation was detected for AR-C579F. Image analyses of the receptors fused to green fluorescent protein showed that the wild-type AR was ligand-dependently translocated into the nucleus in which it formed fine subnuclear foci. Surprisingly, after the addition of dihydrotestosterone, the two mutant ARs initially formed large cytoplasmic dots, many of which were found to be close to mitochondria by electron microscopy. Subsequently, a part of the ligand-bound mutant ARs gradually entered the nucleus to form a smaller number of larger dots, compared with the wild-type AR. Fluorescence recovery after photobleaching analysis revealed that the intranuclear mobility of the mutant ARs decreased, compared with that of the wild-type AR.

Conclusions: These results suggest that the abnormal translocation, localization, and mobility of the mutant ARs may be the cause of AIS in these subjects.

This article has been cited by other articles:

				S. Lenie and J. Smitz Functional AR Signaling Is Evident in an In Vitro Mouse Follicle Culture Bioassay That Encompasses Most Stages of Folliculogenesis Biol Reprod, April 1, 2009; 80(4): 685 - 695. [Abstract] [Full Text] [PDF]

				W. Fan, T. Yanase, Y. Nishi, S. Chiba, T. Okabe, M. Nomura, H. Yoshimatsu, S. Kato, R. Takayanagi, and H. Nawata Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor Endocrinology, December 1, 2008; 149(12): 6028 - 6036. [Abstract] [Full Text] [PDF]

				N. Kaku, K.-i. Matsuda, A. Tsujimura, and M. Kawata Characterization of Nuclear Import of the Domain-Specific Androgen Receptor in Association with the Importin {alpha}/{beta} and Ran-Guanosine 5'-Triphosphate Systems Endocrinology, August 1, 2008; 149(8): 3960 - 3969. [Abstract] [Full Text] [PDF]

				G. N. Corry, M. J. Hendzel, and D. A. Underhill Subnuclear localization and mobility are key indicators of PAX3 dysfunction in Waardenburg syndrome Hum. Mol. Genet., June 15, 2008; 17(12): 1825 - 1837. [Abstract] [Full Text] [PDF]

				M. L. Cutress, H. C. Whitaker, I. G. Mills, M. Stewart, and D. E. Neal Structural basis for the nuclear import of the human androgen receptor J. Cell Sci., April 1, 2008; 121(7): 957 - 968. [Abstract] [Full Text] [PDF]

				K. Sun, V. Montana, K. Chellappa, Y. Brelivet, D. Moras, Y. Maeda, V. Parpura, B. M. Paschal, and F. M. Sladek Phosphorylation of a Conserved Serine in the Deoxyribonucleic Acid Binding Domain of Nuclear Receptors Alters Intracellular Localization Mol. Endocrinol., June 1, 2007; 21(6): 1297 - 1311. [Abstract] [Full Text] [PDF]

				R. L. Arnett-Mansfield, J. D. Graham, A. R. Hanson, P. A. Mote, A. Gompel, L. L. Scurr, N. Gava, A. de Fazio, and C. L. Clarke Focal Subnuclear Distribution of Progesterone Receptor Is Ligand Dependent and Associated with Transcriptional Activity Mol. Endocrinol., January 1, 2007; 21(1): 14 - 29. [Abstract] [Full Text] [PDF]

				N. Z. Lu, S. E. Wardell, K. L. Burnstein, D. Defranco, P. J. Fuller, V. Giguere, R. B. Hochberg, L. McKay, J.-M. Renoir, N. L. Weigel, et al. International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors Pharmacol. Rev., December 1, 2006; 58(4): 782 - 797. [Full Text] [PDF]