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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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N-terminal polyglutamine-containing fragments inhibit androgen receptor transactivation function

Niclas W. Schiffer1 / Jocelyn Céraline2 / F. Ulrich Hartl3 / Sarah A. Broadley4

1Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany

2Université Strasbourg-Faculté de Médecine, EA 3430-Signalisation et Cancer de la Prostate, F-67000 Strasbourg, France

3Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany

4Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany

Corresponding author

Citation Information: Biological Chemistry. Volume 389, Issue 12, Pages 1455–1466, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2008.169, October 2008

Publication History

Received:
2008-08-16
Accepted:
2008-09-01
Published Online:
2008-10-09

Abstract

Several neurodegenerative diseases, including Kennedy's disease (KD), are associated with misfolding and aggregation of polyglutamine (polyQ)-expansion proteins. KD is caused by a polyQ-expansion in the androgen receptor (AR), a key player in male sexual differentiation. Interestingly, KD patients often show signs of mild-to-moderate androgen insensitivity syndrome (AIS) resulting from AR dysfunction. Here, we used the yeast Saccharomyces cerevisiae to investigate the molecular mechanism behind AIS in KD. Upon expression in yeast, polyQ-expanded N-terminal fragments of AR lacking the hormone binding domain caused a polyQ length-dependent growth defect. Interestingly, while AR fragments with 67 Q formed large, SDS-resistant inclusions, the most pronounced toxicity was observed upon expression of 102 Q fragments which accumulated exclusively as soluble oligomers in the 100–600 kDa range. Analysis using a hormone-dependent luciferase reporter revealed that full-length polyQ-expanded AR is fully functional in transactivation, but becomes inactivated in the presence of the corresponding polyQ-expanded N-terminal fragment. Furthermore, the greatest impairment of AR activity was observed upon interaction of full-length AR with soluble AR fragments. Taken together, our results suggest that soluble polyQ-containing fragments bind to full-length AR and inactivate it, thus providing insight into the mechanism behind AIS in KD and possibly other polyglutamine diseases, such as Huntington's disease.

Keywords: androgen receptor; Kennedy's disease; polyglutamine; yeast

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