This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited 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 Brüggenwirth, H. T. Articles by Brinkmann, A. O. Search for Related Content PubMed PubMed Citation Articles by Brüggenwirth, H. T. Articles by Brinkmann, A. O.

Substitution of Ala⁵⁶⁴ in the First Zinc Cluster of the Deoxyribonucleic Acid (DNA)-Binding Domain of the Androgen Receptor by Asp, Asn, or Leu Exerts Differential Effects on DNA Binding¹

Departments of Endocrinology & Reproduction (H.T.B., A.L.M.B., A.O.B.) and Pathology (J.T.), Erasmus University, Rotterdam, The Netherlands; and Pathologie Molèculaire des Recepteurs Nucléaires, INSERM U-439 (J.M.L., C.S.), and Centre de Biochimie Structurale, UMR 9955, Faculté de Pharmacie, CNRS-INSERM-Université Montpellier I (L.C.), Montpellier, France

Address all correspondence and requests for reprints to: Dr. H. T. Brüggenwirth, Department of Endocrinology & Reproduction, Faculty of Medicine and Health Sciences, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: bruggenwirth{at}endov.fgg.eur.nl

In the androgen receptor of a patient with androgen insensitivity, the alanine residue at position 564 in the first zinc cluster of the DNA-binding domain was substituted by aspartic acid. In other members of the steroid receptor family, either valine or alanine is present at the corresponding position, suggesting the importance of a neutral amino acid residue at this site. The mutant receptor was transcriptionally inactive, which corresponded to the absence of specific DNA binding in gel retardation assays, and its inactivity in a promoter interference assay. Two other receptor mutants with a mutation at this same position were created to study the role of position 564 in the human androgen receptor on DNA binding in more detail. Introduction of asparagine at position 564 resulted in transcription activation of a mouse mammary tumor virus promoter, although at a lower level compared with the wild-type receptor. Transcription activation of an (ARE)₂-TATA promoter was low, and binding to different hormone response elements could not be visualized. The receptor with a leucine residue at position 564 was as active as the wild-type receptor on a mouse mammary tumor virus promoter and an (ARE)₂-TATA promoter, but interacted differentially with several hormone response elements in a gel retardation assay. The results of the transcription activation and DNA binding studies could partially be predicted from three-dimensional modeling data. The phenotype of the patient was explained by the negative charge, introduced at position 564.

This article has been cited by other articles:

				P. Farla, R. Hersmus, J. Trapman, and A. B. Houtsmuller Antiandrogens prevent stable DNA-binding of the androgen receptor J. Cell Sci., September 15, 2005; 118(18): 4187 - 4198. [Abstract] [Full Text] [PDF]

				H. J. Dubbink, R. Hersmus, C. S. Verma, H. A. G. M. van der Korput, C. A. Berrevoets, J. van Tol, A. C. J. Ziel-van der Made, A. O. Brinkmann, A. C. W. Pike, and J. Trapman Distinct Recognition Modes of FXXLF and LXXLL Motifs by the Androgen Receptor Mol. Endocrinol., September 1, 2004; 18(9): 2132 - 2150. [Abstract] [Full Text] [PDF]

				G. Buchanan, N. M. Greenberg, H. I. Scher, J. M. Harris, V. R. Marshall, and W. D. Tilley Collocation of Androgen Receptor Gene Mutations in Prostate Cancer Clin. Cancer Res., May 1, 2001; 7(5): 1273 - 1281. [Abstract] [Full Text]

				J.-M. Lobaccaro, N. Poujol, B. Térouanne, V. Georget, S. Fabre, S. Lumbroso, and C. Sultan Transcriptional Interferences between Normal or Mutant Androgen Receptors and the Activator Protein 1--Dissection of the Androgen Receptor Functional Domains Endocrinology, January 1, 1999; 140(1): 350 - 357. [Abstract] [Full Text]

				V. Georget, B. Térouanne, S. Lumbroso, J.-C. Nicolas, and C. Sultan Trafficking of Androgen Receptor Mutants Fused to Green Fluorescent Protein: A New Investigation of Partial Androgen Insensitivity Syndrome J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3597 - 3603. [Abstract] [Full Text]