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Genes & Dev. 14 (4): 422-434

Copyright © 2000 by Cold Spring Harbor Laboratory Press.

Vol. 14, No. 4, pp. 422-434, February 15, 2000

The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies

Brian C. Freeman,1 Sara J. Felts,2 David O. Toft,2 and Keith R. Yamamoto1,3

1 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143-0450 USA; 2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905 USA

Multiple molecular chaperones, including Hsp90 and p23, interact with members of the intracellular receptor (IR) family. To investigate p23 function, we compared the effects of three p23 proteins on IR activities, yeast p23 (sba1p) and the two human p23 homologs, p23 and tsp23. We found that Sba1p was indistinguishable from human p23 in assays of seven IR activities in both animal cells and in yeast; in contrast, certain effects of tsp23 were specific to that homolog. Transcriptional activation by two IRs was increased by expression of any of the p23 species, whereas activation by five other IRs was decreased by Sba1p or p23, and unaffected by tsp23. p23 was expressed in all tissues examined except striated and cardiac muscle, whereas tsp23 accumulated in a complementary pattern; hence, p23 proteins might contribute to tissue-specific differences in IR activities. Unlike Hsp90, which acts on IR aporeceptors to stimulate ligand potency (i.e., hormone-binding affinity), p23 proteins acted on IR holoreceptors to alter ligand efficiencies (i.e., transcriptional activation activity). Moreover, the p23 effects developed slowly, requiring prolonged exposure to hormone. In vitro, p23 interacted preferentially with hormone-receptor-response element ternary complexes, and stimulated receptor-DNA dissociation. The dissociation was reversed by addition of a fragment of the GRIP1 coactivator, suggesting that the two reactions may be in competition in vivo. Our findings suggest that p23 functions at one or more late steps in IR-mediated signal transduction, perhaps including receptor recycling and/or reversal of the response.

[Key Words: intracellular receptor; ligand efficacy; molecular chaperone; p23]

3 Corresponding author.

GENES & DEVELOPMENT 14:422-434 © 2000 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/00 $5.00

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