{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:55:38Z","timestamp":1789210538183,"version":"build-2803163510"},"reference-count":30,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,4,17]]},"abstract":"<jats:p>Polyglutamine tract expansion in androgen receptor is a recognized cause of spinal and bulbar muscular atrophy (SBMA), an X-linked motor neuronopathy. Similar mutations have been identified in proteins associated with other neurodegenerative diseases. Recent studies have shown that amplified polyglutamine repeat stretches form cellular aggregates that may be markers for these neurodegenerative diseases. Here we describe conditions that lead to aggregate formation by androgen receptor with polyglutamine stretch amplification. In transfection experiments, the mutant, compared with the wild-type receptor, was delayed in its cytoplasmic\u2013nuclear translocation and formed large cytoplasmic aggregates in the presence of androgen. The cytoplasmic environment appears crucial for this aggregation, since retention of both the wild-type and mutant receptors in this cellular compartment by the deletion of their nuclear localization signals resulted in massive aggregation. Conversely, rapid nuclear transport of both receptors brought about by deletion of their ligand binding domains did not result in aggregate formation. However, androgen antagonists that altered the conformation of the ligand binding domain and promoted varying rates of cytoplasmic\u2013nuclear translocation all inhibited aggregate formation. This demonstrates that in addition to the cytoplasmic localization, a distinct contribution of the ligand binding domain of the receptor is necessary for the aggregation. The finding that antiandrogens inhibit aggregate formation may provide the basis for in vivo determination of the role of these structures in SBMA.<\/jats:p>","DOI":"10.1083\/jcb.149.2.255","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:45:41Z","timestamp":1027701941000},"page":"255-262","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Cytoplasmic Localization and the Choice of Ligand Determine Aggregate Formation by Androgen Receptor with Amplified Polyglutamine Stretch"],"prefix":"10.1083","volume":"149","author":[{"given":"Matthias","family":"Becker","sequence":"first","affiliation":[{"name":"aForschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Martin","sequence":"additional","affiliation":[{"name":"aForschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Schneikert","sequence":"additional","affiliation":[{"name":"aForschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald F.","family":"Krug","sequence":"additional","affiliation":[{"name":"aForschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.B.","family":"Cato","sequence":"additional","affiliation":[{"name":"aForschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2000,4,17]]},"reference":[{"key":"2023072902033639000_Binghametal1995","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/ng0295-191","article-title":"Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice","volume":"9","author":"Bingham","year":"1995","journal-title":"Nat. Genet."},{"key":"2023072902033639000_Butleretal1998","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/hmg\/7.1.121","article-title":"Truncated forms of the androgen receptor are associated with polyglutamine expansion in X-linked spinal and bulbar muscular atrophy","volume":"7","author":"Butler","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"2023072902033639000_Chamberlainetal1994","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1093\/nar\/22.15.3181","article-title":"The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function","volume":"22","author":"Chamberlain","year":"1994","journal-title":"Nucleic Acids Res."},{"key":"2023072902033639000_Culigetal1993","first-page":"1541","article-title":"Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone","volume":"7","author":"Culig","year":"1993","journal-title":"Mol. Endocrinol."},{"key":"2023072902033639000_Daneketal1994","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1007\/BF00190748","article-title":"Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy","volume":"72","author":"Danek","year":"1994","journal-title":"Clin. 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Med."},{"key":"2023072902033639000_Gutekunstetal1999","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1523\/JNEUROSCI.19-07-02522.1999","article-title":"Nuclear and neuropil aggregates in Huntington's diseaserelationship to neuropathology","volume":"19","author":"Gutekunst","year":"1999","journal-title":"J. Neurosci."},{"key":"2023072902033639000_Huynhetal1999","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/1531-8249(199902)45:2<232::AID-ANA14>3.0.CO;2-7","article-title":"Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer's disease and spinocerebellar ataxia 2","volume":"45","author":"Huynh","year":"1999","journal-title":"Ann. Neurol."},{"key":"2023072902033639000_Igarashietal1998","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng0298-111","article-title":"Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch","volume":"18","author":"Igarashi","year":"1998","journal-title":"Nat. Genet."},{"key":"2023072902033639000_Ishikawaetal1999","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/hmg\/8.7.1185","article-title":"Abundant expression and cytoplasmic aggregations of \u03b11A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6","volume":"8","author":"Ishikawa","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"2023072902033639000_Karpujetal1999","doi-asserted-by":"crossref","first-page":"7388","DOI":"10.1073\/pnas.96.13.7388","article-title":"Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei","volume":"96","author":"Karpuj","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072902033639000_Kooetal1999","doi-asserted-by":"crossref","first-page":"9989","DOI":"10.1073\/pnas.96.18.9989","article-title":"Amyloid diseaseabnormal protein aggregation in neurodegeneration","volume":"96","author":"Koo","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072902033639000_KuilandMulder1994","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1016\/0303-7207(94)90112-0","article-title":"Mechanism of antiandrogen actionconformational changes of the receptor","volume":"102","author":"Kuil","year":"1994","journal-title":"Mol. Cell. 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Pathol."},{"key":"2023072902033639000_Linetal1999","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0896-6273(00)81104-6","article-title":"Expanding our understanding of polyglutamine diseases through mouse models","volume":"24","author":"Lin","year":"1999","journal-title":"Neuron."},{"key":"2023072902033639000_MerryandFischbeck1998","first-page":"101","article-title":"Genetics and molecular biology of the androgen receptor CAG repeat","volume-title":"Genetic Instability and Hereditary Neurological Disease","author":"Merry","year":"1998"},{"key":"2023072902033639000_Neuschmid-Kasparetal1996","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0303-7207(95)03741-1","article-title":"CAG-repeat expansion in androgen receptor in Kennedy's disease is not a loss of function mutation","volume":"177","author":"Neuschmid-Kaspar","year":"1996","journal-title":"Mol. Cell. 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Sci."},{"key":"2023072902033639000_Peterzieletal1999","doi-asserted-by":"crossref","first-page":"6322","DOI":"10.1038\/sj.onc.1203032","article-title":"Rapid signalling by androgen receptor in prostate cancer cells","volume":"18","author":"Peterziel","year":"1999","journal-title":"Oncogene."},{"key":"2023072902033639000_Ross1997","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0896-6273(00)80405-5","article-title":"Intranuclear neuronal inclusionsa common pathogenic mechanism for glutamine-repeat neurodegenerative diseases?","volume":"19","author":"Ross","year":"1997","journal-title":"Neuron."},{"key":"2023072902033639000_Saudouetal1998","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0092-8674(00)81782-1","article-title":"Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions","volume":"95","author":"Saudou","year":"1998","journal-title":"Cell."},{"key":"2023072902033639000_Sisodia1998","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0092-8674(00)81743-2","article-title":"Nuclear inclusions in glutamine repeat disordersare they pernicious, coincidental, or beneficial?","volume":"95","author":"Sisodia","year":"1998","journal-title":"Cell."},{"key":"2023072902033639000_Stenoienetal1999","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1093\/hmg\/8.5.731","article-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","volume":"8","author":"Stenoien","year":"1999","journal-title":"Hum. 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