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Human Molecular Genetics, 2002, Vol. 11, No. 17 1967-1976
© 2002 Oxford University Press

Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor

Andrew P. Lieberman1,*, George Harmison1, Andrew D. Strand2, James M. Olson2 and Kenneth H. Fischbeck1

1Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA and 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA

Received March 12, 2002; Accepted May 22, 2002

Kennedy's disease is a degenerative disease of motor neurons in which the causative mutation is expansion of a CAG/polyglutamine tract near the 5' end of the androgen receptor gene. The mutant protein misfolds, aggregates, and interacts abnormally with other proteins, leading to a novel, toxic gain of function and an alteration of normal function. We used a cell culture model to explore the mechanisms underlying the alterations in androgen receptor function conferred by the mutation. Here we show that cells expressing the wild-type androgen receptor with 24 CAG repeats respond to ligand by showing trophic effects including prolonged survival in low serum, whereas cells expressing the mutant receptor with 65 CAG repeats do not show a robust trophic response. This partial loss of function correlates with decreased levels of the mutant protein due to its preferential degradation by the ubiquitin–proteasome pathway. Expression analysis using oligonucleotide arrays confirms that the mutant receptor has undergone a partial loss of function, and fails to regulate a subset of genes whose expression is normally affected by ligand activation of the wild-type receptor. The mutant receptor has also undergone several functionally important post-translational modifications in the absence of ligand that the wild-type receptor undergoes in the presence of ligand, including acetylation and phosphorylation. These modifications correlate with a ligand-independent gain of function exhibited by the mutant receptor in expression analysis. Our findings suggest that polyglutamine expansion alters androgen receptor function by promoting its degradation and by modifying its activity as a transcription factor.

* To whom correspondence should be addressed at: Department of Pathology, University of Michigan School of Medicine, 1301 Catherine, 4233 Medical Science 1, Ann Arbor, MI 48109-0602, USA. Tel.: +1 7349361887; Fax: +1 7347636476; Email: liebermn{at}umich.edu


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