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Polyglutamine-Expanded Androgen Receptors Form Aggregates That Sequester Heat Shock Proteins, Proteasome Components and SRC-1, and Are Suppressed by the HDJ-2 Chaperone

Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggreg...

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Published in:Human molecular genetics 1999-05, Vol.8 (5), p.731-741
Main Authors: Stenoien, David L., Cummings, Chris J., Adams, Henry P., Mancini, Maureen G., Patel, Kavita, DeMartino, George N., Marcelli, Marco, Weigel, Nancy L., Mancini, Michael A.
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container_issue 5
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container_title Human molecular genetics
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creator Stenoien, David L.
Cummings, Chris J.
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Weigel, Nancy L.
Mancini, Michael A.
description Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggregates. Electron microscopy reveals both types of aggregates to have a similar ultrastructure. ARQ48 aggregates sequester mitochondria and steroid receptor coactivator 1 and stain positively for NEDD8, Hsp70, Hsp90 and HDJ-2/HSDJ. Co-expression of HDJ-2/HSDJ significantly represses aggregate formation. ARQ48 aggregates also label with antibodies recognizing the PA700 proteasome caps but not 20S core particles. These results suggest that ARQ48 accumulates due to protein misfolding and a breakdown in proteolytic processing. Furthermore, the homeostatic disturbances associated with aggregate formation may affect normal cell function.
doi_str_mv 10.1093/hmg/8.5.731
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subjects Adenosine Triphosphate - metabolism
Biological and medical sciences
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Nucleus - metabolism
Cysteine Endopeptidases - metabolism
Cytoplasm - metabolism
Cytoplasm - ultrastructure
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Green Fluorescent Proteins
Heat-Shock Proteins - genetics
Heat-Shock Proteins - metabolism
HeLa Cells - drug effects
HeLa Cells - metabolism
Histone Acetyltransferases
HSP40 Heat-Shock Proteins
Humans
Luminescent Proteins - genetics
Luminescent Proteins - metabolism
Medical sciences
Mitosis
Multienzyme Complexes - metabolism
NEDD8 Protein
Neurology
Nuclear Receptor Coactivator 1
Peptides - genetics
Peptides - metabolism
Proteasome Endopeptidase Complex
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Receptors, Steroid - genetics
Receptors, Steroid - metabolism
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Transcription Factors - metabolism
Ubiquitins - genetics
Ubiquitins - metabolism
title Polyglutamine-Expanded Androgen Receptors Form Aggregates That Sequester Heat Shock Proteins, Proteasome Components and SRC-1, and Are Suppressed by the HDJ-2 Chaperone
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