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Mol Cell Biol, June 1998, p. 3330-3339, Vol. 18, No. 6
Laboratory of Biochemistry, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20892-4255
Received 17 October 1997/Returned for modification 15 December
1997/Accepted 6 March 1998
The ubiquitous molecular chaperone Hsp90 acts in concert with a
cohort of associated proteins to facilitate the functional maturation
of a number of cellular signaling proteins, such as steroid hormone
receptors and oncogene tyrosine kinases. The Hsp90-associated protein
p23 is required for the assembly of functional steroid aporeceptor
complexes in cell lysates, and Hsp90-binding ansamycin antibiotics
disrupt the activity of Hsp90-dependent signaling proteins in cultured
mammalian cells and prevent the association of p23 with Hsp90-receptor
heterocomplexes; these observations have led to the hypotheses that p23
is required for the maturation of Hsp90 target proteins and that
ansamycin antibiotics abrogate the activity of such proteins by
disrupting the interaction of p23 with Hsp90. In this study, I
demonstrate that ansamycin antibiotics disrupt the function of Hsp90
target proteins expressed in yeast cells; prevent the assembly of Sba1,
a yeast p23-like protein, into steroid receptor-Hsp90 complexes; and
result in the assembly of receptor-Hsp90 complexes that are defective
for ligand binding. To assess the role of p23 in Hsp90 target protein
function, I show that the activity of Hsp90 target proteins is
unaffected by deletion of SBA1. Interestingly, steroid
receptor activity in cells lacking Sba1 displays increased sensitivity
to ansamycin antibiotics, and this phenotype is rescued by the
expression of human p23 in yeast cells. These findings indicate that
Hsp90-dependent signaling proteins can achieve a functional
conformation in vivo in the absence of p23. Furthermore, while the
presence of p23 decreases the sensitivity of Hsp90-dependent processes
to ansamycin treatment, ansamycin antibiotics disrupt signaling through
some mechanism other than altering the Hsp90-p23 interaction.
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Genetic and Biochemical Analysis of p23 and
Ansamycin Antibiotics in the Function of Hsp90-Dependent
Signaling Proteins
*
Present address: University of California-San
Francisco, Department of Medicine, San Francisco, CA 94143. Phone:
(415) 661-4775. Fax: (415) 476-6129. E-mail:
bohens{at}itsa.ucsf.edu.
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