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Human Molecular Genetics Advance Access originally published online on April 30, 2007
Human Molecular Genetics 2007 16(13):1593-1603; doi:10.1093/hmg/ddm109
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Published by Oxford University Press 2007
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity

Isabella Palazzolo1, Barrington G. Burnett1, Jessica E. Young2, Phebe L. Brenne1, Albert R. La Spada2, Kenneth H. Fischbeck1, Brian W. Howell1 and Maria Pennuto1,*

1 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA and 2 Departments of Laboratory Medicine, Medicine and Neurology, and Center for Neurogenetics and Neurotherapeutics, University of Washington, Seattle, WA, USA

* To whom correspondence should be addressed. Tel: +1 3014359288; Fax: +1 3014803365; Email: pennutom{at}ninds.nih.gov

Received March 23, 2007; Accepted April 19, 2007

Spinal and bulbar muscular atrophy (SBMA) is a progressive neurodegenerative disease caused by an expansion of the polyglutamine tract in the androgen receptor (AR). Here, we investigated the regulation of AR phosphorylation in order to understand factors that may modify SBMA disease progression. We show that expanded polyglutamine AR is phosphorylated by Akt. Substitution of the AR at two Akt consensus sites, S215 and S792, with aspartate, which mimics phosphorylation, reduces ligand binding, ligand-dependent nuclear translocation, transcriptional activation and toxicity of expanded polyglutamine AR. Co-expression of constitutively active Akt and the AR has similar consequences, which are blocked by alanine substitutions at residues 215 and 792. Furthermore, in motor neuron-derived MN-1 cells toxicity associated with polyglutamine-expanded AR is rescued by co-expression with Akt. Insulin-like growth factor-1 (IGF-1) stimulation, which activates several cell survival promoting pathways, also reduces toxicity of the expanded polyglutamine AR in MN-1 cells, in a manner dependent upon phospho-inositol-3-kinase. IGF-1 rescue of AR toxicity is diminished by alanine substitutions at the Akt consensus sites. These results highlight potential targets for therapeutic intervention in SBMA.


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