The effect of polyglutamine expansion in the human androgen receptor on its ability to suppress beta-catenin-Tcf/Lef dependent transcription.
Expansion of the polyglutamine repeat region of the androgen receptor (AR) results in Kennedy's disease, a neurological disorder typified by degeneration of motor neurons in the brain stem and spinal cord. As the AR has been shown to inhibit beta-catenin dependent (Wnt) signalling we asked if expansion of the polyglutamine repeats might affect this property of the protein. Using the TOPflash/FOPflash reporter assay we found that a pathogenic form of the AR containing 51 glutamine repeats showed a consistent, though minimal, reduction in its ability to inhibit beta-catenin-mediated transcription, in comparison to a non-pathogenic form with 20 repeats. A reduced ability to inhibit Wnt signalling may thus contribute in part to the underlying aetiology of Kennedy's disease.
Cullen
D A
DA
Department of Neurology, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
Killick
R
R
Leigh
P N
PN
Gallo
J-M
JM
D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D007668:Kidney / Q000166:cytology; D051821:Lymphoid Enhancer-Binding Factor 1; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000503:physiopathology; D010455:Peptides / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D010455:Peptides; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C097188:polyglutamine