The role of the Hsp90 chaperone machine in androgen and estrogen receptor action.
Item
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Title
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The role of the Hsp90 chaperone machine in androgen and estrogen receptor action.
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Identifier
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AAI9908315
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identifier
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9908315
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Creator
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Fliss, Albert Edward, Jr.
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Contributor
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Adviser: Avrom Caplan
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Date
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1998
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular | Biology, Genetics
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Abstract
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Hsp90 along with its binding proteins or co-chaperones comprises the Hsp90 chaperone machine. This chaperone machine is important in the regulation of steroid hormone receptor activation and is functionally conserved from yeast to mammals. In the present study, the yeast model system was utilized to determine the role of Hsp90 and two of its co-chaperones Ydj1 and Cdc37 in AR and ER hormone binding and subsequent activation. Results from direct hormone binding and ligand competition assays suggest that both Hsp90 and Ydj1 are required for hormone binding to both the AR and ER. In the absence of functional Hsp90, AR and ER were decreased in their ability to bind hormone. Likewise, the ability of hormone antagonist to compete for hormone binding to either receptor was altered. In the absence of Ydj1 or functional Hsp90, the AR antagonist HF was converted from a weak competitor of R1881 binding to a potent one. In contrast, the ER antagonist 4-OHT was converted from a competitor to a potentiator of DES and E2 binding to the ER in the absence of functional Hsp90, whereas, it neither competes nor potentiates DES binding in the absence of Ydj1. The defect in AR hormone binding seen in the {dollar}\Delta{dollar}ydj1 strain is mediated via the J domain of Ydj1 and Hdj2 was able to fully complement the AR signaling defect.;Previous studies have demonstrated that Cdc37 is also part of the Hsp90 chaperone machine. In this study, it was demonstrated that hormone dependent AR signaling was grossly defective in a Cdc37 mutant strain and this defect was mediated via the HBD. However, in contrast to Hsp90 and Ydj1, the Cdc37 defect was not in hormone binding. This defect was seen to a lesser extent with GR and ER, suggesting that Cdc37 differentially regulates steroid hormone receptor activation.;In summary, Hsp90 and Ydj1 are required for hormone binding to the AR and ER. Cdc37 is differentially required for hormone dependent activation, however, this defect is not in hormone binding. This demonstrates that components of the chaperone machine can act before or after hormone binding.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
