Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity.
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.
Palazzolo
Isabella
I
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.
Burnett
Barrington G
BG
Young
Jessica E
JE
Brenne
Phebe L
PL
La Spada
Albert R
AR
Fischbeck
Kenneth H
KH
Howell
Brian W
BW
Pennuto
Maria
M
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D042622:DNA Repeat Expansion / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015533:Transcriptional Activation
D007334:Insulin-Like Growth Factor I; D008024:Ligands; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; C097188:polyglutamine