The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/C(Cdh1) ubiquitin ligase complex.
Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture. We show that both wild-type and mutant AR physically interact with the APC/C(Cdh1) complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/C(Cdh1) by mutant but not wild-type AR in PC12 cells results in enhanced neurite outgrowth which is typically followed by rapid neurite retraction and mitotic entry. Our data indicate a role of AR in neuronal differentiation through regulation of APC/C(Cdh1) and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm 17177, Sweden.|National Institute of Neurological Disorders and Stroke, Neurogenetics Branch, Bethesda, MD 20892, USA.
Laura C
LC
Bott
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm 17177, Sweden.
Florian A
FA
Salomons
Flow Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Dragan
D
Maric
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Yuhong
Y
Liu
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Diane
D
Merry
National Institute of Neurological Disorders and Stroke, Neurogenetics Branch, Bethesda, MD 20892, USA.
Kenneth H
KH
Fischbeck
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm 17177, Sweden.
Nico P
NP
Dantuma
D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002352:Carrier Proteins; D002453:Cell Cycle; D009154:Mutation; D016501:Neurites / Q000378:metabolism; D016716:PC12 Cells; D059748:Proteolysis; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D011944:Receptors, Androgen; D064173:Anaphase-Promoting Complex-Cyclosome