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dc.contributor.authorBuchanan, G.en
dc.contributor.authorRicciardelli, C.en
dc.contributor.authorHarris, J.en
dc.contributor.authorPrescott, J.en
dc.contributor.authorYu, Z.en
dc.contributor.authorJia, L.en
dc.contributor.authorButler, L.en
dc.contributor.authorMarshall, V.en
dc.contributor.authorScher, H.en
dc.contributor.authorGerald, W.en
dc.contributor.authorCoetzee, G.en
dc.contributor.authorTilley, W.en
dc.identifier.citationCancer Research, 2007; 67(20):10087-10096en
dc.description.abstractAlthough the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine-rich tetratricopeptide repeat containing protein alpha (alphaSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that alphaSGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of alphaSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of alphaSGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/alphaSGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression, particularly in a low-hormone environment. These findings implicate alphaSGT as a molecular rheostat of in vivo signaling competence by the AR, and provide new insight into the determinants of androgen sensitivity during prostate cancer progression.en
dc.description.statementofresponsibilityGrant Buchanan, Carmela Ricciardelli, Jonathan M. Harris, Jennifer Prescott, Zoe Chiao-Li Yu, Li Jia, Lisa M. Butler, Villis R. Marshall, Howard I. Scher, William L. Gerald, Gerhard A. Coetzee and Wayne D. Tilleyen
dc.publisherAmer Assoc Cancer Researchen
dc.rights© 2007 American Association for Cancer Researchen
dc.subjectCytoplasm; Humans; Prostatic Neoplasms; Neoplasm Metastasis; Disease Progression; Carrier Proteins; Receptors, Androgen; Signal Transduction; Transcription, Genetic; Amino Acid Sequence; Models, Molecular; Molecular Sequence Data; Male; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteinsen
dc.titleControl of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein αen
dc.title.alternativeControl of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein alphaen
dc.typeJournal articleen
pubs.library.collectionMedicine publicationsen
dc.identifier.orcidRicciardelli, C. [0000-0001-7415-1854]en
dc.identifier.orcidButler, L. [0000-0003-2698-3220]en
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]en
Appears in Collections:Medicine publications

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