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