Molecular Chaperone Interactions with Steroid Receptors: an Update
Joyce Cheung and
David F. Smith
Department of Biochemistry and Molecular Biology Mayo Clinic
Scottsdale Scottsdale, Arizona 85259
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INTRODUCTION
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In the 3 yr since William Pratt and David Toft
published their comprehensive review of chaperone interactions with
steroid receptors (1 ), progress has been made on several fronts that
gives a better appreciation for the range of functions that chaperones
serve in mediating steroid signaling. Steroid receptors remain the best
characterized examples of an ever growing assortment of cytoplasmic and
nuclear proteinsdiverse representatives from multiple signal
transduction pathwaysthat rely on molecular chaperones for folding,
stabilization, or functional modulation. Chaperone targets include
multiple tyrosine and serine/threonine kinases (2 ), the arylhydrocarbon
receptor (3 4 5 6 7 8 ), the heat shock transcription factor (9 10 11 ), common
p53 mutants (Ref. 12 and references therein), nitric oxide synthase
(13 14 15 ), and telomerase (16 )an impressive list of "hot topic"
proteins. Often, investigators have restricted their interpretations of
chaperone interactions as a simple reflection of folding insufficiency
by the target protein. Supporting this view are two major facts: 1)
chaperones generally function in overseeing protein folding processes
and 2) it is commonly observed that the target signaling protein will
fail to achieve its functional state and is more rapidly degraded by
the proteolytic machinery when major chaperone interactions are
disrupted. As with other targets, steroid receptors display functional
instabilities when deprived of certain chaperones, and thus fit the
mold of unstable protein target, but it is hoped that the reader will
be convinced by recent findings that chaperone interactions with
steroid receptors and, by extension, with unrelated signaling targets,
serve a variety of functions that go beyond the simple explanation of
folding insufficiency.
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ASSEMBLY OF STEROID RECEPTOR-CHAPERONE COMPLEXES: THE BASICS
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In the absence of hormone binding or other activating signals,
steroid receptors typically exist in heteromeric complexes with heat
shock proteins (Hsp) and additional components of the molecular
chaperone machinery. In a pioneering study by Toft and his colleagues
(17 ), hormone-free chicken progesterone receptor (PR) was found to
readily assemble with chaperones in rabbit reticulocyte lysate, and the
resulting PR complexes were similar in chaperone composition to native
PR complexes (17 ). Taking advantage of reticulocyte lysate as a
cell-free assembly medium, further extensive characterizations have
been undertaken by the laboratories of Toft and Smith, focusing
on PR complexes, and by Pratts laboratory, studying glucocorticoid
receptor (GR) complexes, to identify assembly components, to delineate
biochemical processes, and to understand the functional consequences of
receptor-chaperone interactions.
As thoroughly reviewed by Pratt and Toft (1 ), amended by more recent
studies (18 19 20 21 ), and briefly summarized here, the assembly pathway for
steroid receptor-chaperone complexes can involve at least 10 chaperone
components, five of which are obligatory in vitro for
maturation of hormone binding ability by GR and PR. Three of the
obligate factors are constitutively expressed forms of Hsp70,
DnaJ/Hsp40, and Hsp90. Two cochaperone proteins are additionally
required: the Hsp90-binding protein p23 and Hsp70/Hsp90 organizing
protein (Hop), which brings Hsp70 and Hsp90 together in a common
complex. Two additional Hsp70 binding cochaperones, Hsp70 interacting
protein (Hip) and BAG-1, have been identified in receptor complexes,
but these are nonessential in minimal in vitro
hormone-binding assays. There are four additional proteins, also
nonessential in minimal in vitro assays, that bind Hsp90 and
are recovered in native receptor complexes. These are the FK506-binding
immunophilins FKBP52 and FKBP51, the cyclosporin-A-binding immunophilin
cyclophilin 40 (Cyp40), and the protein phosphatase PP5. Each competes
with Hop for binding Hsp90, and, like Hop, each contains a similar
tetratricopeptide repeat (TPR) domain that mediates their competitive
binding to Hsp90.
As in many chaperone processes, ATP is required for assembly of
receptor-chaperone complexes. Hsp70 and Hsp90 are both ATP-binding
proteins with weak ATPase activity that is necessary for their
chaperone functions and influences their interactions with various
cochaperone proteins. For Hsp70, ATP hydrolysis and nucleotide exchange
regulate its binding and release from misfolded substrates.
Furthermore, Hop and Hip only associate with the ADP-bound form of
Hsp70. For Hsp90, Hop associates preferentially with its ADP-bound form
while p23 binds exclusively to ATP-bound Hsp90.
In complete reticulocyte lysate, free receptor initially associates
with Hsp70 and Hsp40. Hsp70 and Hsp40 can bind each other and often
function in a coordinate manner to facilitate general protein folding
processes in eukaryotes (Refs. 22 23 ; recently reviewed in Ref.
24 ). This early step is dependent on Hsp70 ATPase activity and leads to
the ADP-dependent association of Hip and Hop with Hsp70. Since Hop
binds independently to Hsp90, it functions as an adaptor in binding
Hsp70 to introduce Hsp90 to the receptor complex. In a manner
stabilized by the ATP-dependent association of Hsp90 with p23, Hsp90
somehow becomes directly associated with the receptor ligand- binding
domain, promoting and stabilizing a conformational change that
establishes high affinity hormone binding. In this functionally mature
receptor complex, Hsp90-associated Hop has been replaced by one of the
other TPR proteins. Functions for these immunophilin-like components in
receptor complexes have not been defined, but receptor-specific
preferences for these proteins hint at possible functional
distinctions, and one case is discussed further below. As mentioned
previously, GR and PR assembly studies using purified components to
reconstitute the assembly system have established that Hsp70, Hsp40,
Hop, Hsp90, and p23 are minimally required to establish receptors that
are competent for binding their respective hormones with high affinity
and efficiency. However, these studies do not exclude the potential
importance of other receptor-associated chaperone components in the
more complex and physiologically relevant cellular environment.
Considerable effort has gone toward understanding the mechanisms
underlying complex chaperone-chaperone interactions that mediate the
ordered assembly of functionally competent receptor complexes. Much is
now known about structural motifs that mediate chaperone-chaperone
interactions (reviewed in Ref. 25 ), but much remains to be learned
about transitional assembly states, kinetics, and regulatory aspects of
these interactions.
As a final background note, reticulocyte lysate is thought to provide a
physiologically relevant experimental system for studying assembly of
receptor complexes, even to the extent of approximating what goes on in
the nuclear compartment where many unactivated steroid receptor
complexes reside before hormone-dependent dissociation.
Receptor-associated chaperones are, by and large, very highly conserved
and constitutively expressed in many cell types. Moreover, it has long
been recognized that Hsp70, Hsp90, FKBP52, and Hsp40 forms can exist in
the nuclear compartment (26 27 28 29 ), although Hsp70 and Hsp90 typically
exist at much higher concentrations in the cytoplasm. The subcellular
distribution of other receptor-associated chaperone components has not
been carefully examined, but some fraction of these proteins is likely
also to exist in the nuclear compartment.
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MONKEY BUSINESS
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As G. P. Chrousos, his colleagues, and others have
extensively demonstrated (reviewed in Ref. 30 ), New World primates, as
compared with humans and other Old World primates, typically have
markedly higher circulating levels of cortisol and, less markedly,
estrogen, progesterone, mineralocorticoids, androgen, and vitamin D. In
particular, the squirrel monkey (Saimiri boliviensis
boliviensis) has been studied as a model for cortisol resistance
(30 31 32 ). As might be expected, squirrel monkey (SM) GR has a lowered
affinity for cortisol in SM tissues; surprisingly, however, expression
of a SM-GR cDNA in reticulocyte lysate results in a high-affinity
receptor (33 ). Also, monkey cell extracts had been found to lower the
affinity of human GR for hormone (34 ). These findings suggested that
nonreceptor cytoplasmic factors in SM cells are responsible for lowered
hormone binding affinity. One such factor has recently been identified
as FKBP51 (35 ), one of the large immunophilins found in mature steroid
receptor complexes (36 ).
The immunophilins participating in receptor complexes belong to two
pharmacologically important protein families: the FK506-binding
proteins (FKBP) and the cyclosporin A-binding cyclophilins (for recent
reviews see Refs. 37 38 39 ). The potent immunosuppression induced by
FK506 is mediated primarily by the small immunophilin FKBP12 (40 ) and
inhibition of the protein phosphatase calcineurin (41 ); likewise, the
immunosuppressant cyclosporin A primarily functions through the small
cyclophilin CypA and calcineurin (40 ). The potential modulation of
steroid receptor activities via FK506, cyclosporin, or
related compounds has been the subject of several studies (reviewed in
Ref. 1 ) from which no general conclusion can be drawn. Alterations in
steroid signaling have been observed in cells treated with
immunosuppressant drugs, but the effect has alternately been
potentiation or attenuation of steroid-dependent gene expression.
Furthermore, it has been difficult to attribute drug effects in intact
cells directly to receptor-associated immunophilins, leaving open the
possibility for indirect drug actions, e.g. through
inhibition of membrane transporters that influence intracellular
glucocorticoid levels (42 ), or general phosphorylation events mediated
by calcineurin. In heterologous yeast models, vertebrate steroid
receptor function is disrupted by loss of the yeast Cyp40 homolog Cpr7
(43 ), but such a striking dependence on receptor-associated Cyp40 has
not been observed in native vertebrate systems. There are no
counterparts to FKBP51 or FKBP52 apparent from the Saccharomyces
cerevisiae genomic sequence.
As noted above, a biological role for vertebrate FKBP51 has recently
been suggested from studies of cytoplasmic factors that reduce GR
affinity for cortisol in SM cells. Scammell and colleagues (35 )
reasoned that one of the molecular chaperones, whose interactions with
GR were known to be required for maintaining receptor hormone binding
ability, might be distinctively structured or expressed in SM cells. By
Western immunostain comparisons for the cytosolic content of nine
receptor-associated chaperone components in human and SM lymphocyte
extracts, most components were present at roughly equivalent levels.
The standouts were the FKBPs, where the amount of FKBP51 was more than
10-fold greater in the monkey sample while FKBP52 was only half the
human level. Functional experiments demonstrated that SM-FKBP51
elicited a greater than 10-fold drop in the hormone binding affinity of
human and rodent GR, approximating the affinity observed for SM-GR in
SM cells. Similarly, human FKBP51 was found to reduce GR hormone
binding affinity, but only about 5-fold. Deduced amino acid sequences
for FKBP51 from human, mouse, and SM are about 95% identical, but
fewer than five amino acid changes in the C-terminal region of
SM-FKBP51 appear to be responsible for the greater depression of GR
hormone binding affinity (J. Scammell and D. F. Smith,
unpublished).
Unexpectedly, the reduction of GR binding affinity was completely
reversed by FK506, which was shown to selectively stimulate
dissociation of FKBP51, but not FKBP52, from GR complexes (35 ).
Distinctive interactions by the two receptor-associated FKBPs are
further indicated by FKBP51s preferential retention in GR complexes
when compared with FKBP52 or Cyp40 (20 ). Interestingly, there is an
even greater retention of SM-FKBP51 in receptor complexes (D. F.
Smith, unpublished). In summary, FKBP52 is underexpressed in SM tissues
relative to human, FKBP51 is overexpressed, SM-FKBP51 in GR complexes
lowers the receptor affinity for hormone, and SM-FKBP51 contains
mutations that greatly favor its association with GR complexesa
combination of conditions that promote cortisol resistance.
Lending a more general relevance to FKBP51s influence on
glucocorticoid signaling, Baughman, Bourgois, and co-workers (44 45 46 )
found independently that FKBP51 expression in mouse thymocytes is
inducible by glucocorticoids. In unpublished results, our laboratory
has found that FKBP51 protein levels are elevated by dexamethasone
treatment in each of several GR-expressing cell lines, so the
inducibility of FKBP51 may be a general phenomenon. Since human FKBP51
will lower human GR affinity for hormone (35 ), it appears that FKBP51
could serve to attenuate cortisol responses in hormone-conditioned
tissues. These relationships between FKBP51 and GR signaling are
illustrated in Fig. 1
. In combination
with the ability of FK506 to inhibit FKBP51 association with GR and
thus maintain higher affinity for hormone, there may be opportunities
to take pharmacological advantage of this system, e.g. in
lowering the effective dose for chronically administered glucocorticoid
agonists. The broader lesson to be learned from FKBP51 studies is that
chaperones present in steroid receptor or other signaling protein
complexes can have physiologically relevant modulatory effects on the
protein function that go beyond the folding and stabilization of a
nonnative substrate.

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Figure 1. FKBP51 Influences on Glucocorticoid Signaling
In the absence of hormone, GR exists in a complex with a dimer of
Hsp90, a subunit of p23, and any one of several immunophilin-related
proteins (I). In the presence of immunophilins other than FKBP51, GR
has high affinity for hormone (top panel).
Glucocorticoids stimulate expression of FKBP51, enhancing the
likelihood for some period of time after hormone withdrawal that GR
complexes will contain FKBP51 and have a lowered affinity for
subsequent hormone exposures (middle panel). In squirrel
monkeys, FKBP51 is constitutively expressed at high levels and more
greatly depresses GRs affinity for hormone (bottom
panel).
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AFTER HORMONE BINDS
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A common functional basis for steroid receptor-chaperone
interactions has been the establishment and maintenance of the
receptors unstable hormone binding conformation. One should note,
however, that a continual reliance on chaperones for hormone binding
has been demonstrated only for GR (47 ), PR (48 ), and mineralocorticoid
receptor (49 ). Estrogen receptor (ER) and androgen receptor (AR) have
more stable hormone binding conformations in the absence of Hsp90 and
other chaperones even though they, like other steroid receptors, are
recovered from unstimulated cells in similar chaperone complexes. There
could well be a cellular requirement for chaperones to assist with the
initial folding of nascent receptor polypeptides, perhaps even for
nuclear receptors that are not otherwise isolated in chaperone
complexes (50 ), but this folding requirement does not readily explain
the extended presence of chaperones in ER and AR complexes. Another
likely role for receptor-associated chaperones is to assist in the
functional repression of receptors by inhibiting their abilities to
bind DNA, dimerize, and interact with transcriptional coregulatory
proteins in the absence of ligand binding or other stimulatory signal.
This repressive action of chaperones probably forms the basis for
liganddependent, positional-independent inhibition of activity in
chimeric proteins composed of a steroid receptor ligand-binding domain
fused to a heterologous protein (51 ). As discussed above for FKBP51,
chaperone components can also modulate receptor affinity for ligand.
However, beyond these functional interactions with unactivated
receptors, there is evidence that chaperones are important in
regulating steroid receptor function subsequent to hormone binding.
Given the complexity of protein-protein and protein-DNA interactions in
the promoter region of steroid-responsive genes, it would not be
surprising to find that chaperones transiently participate in chromatin
remodeling or establishing the multiple linkages between receptor and
other proteins that influence a genes transcriptional status, yet
there have been few studies addressing the potential role of chaperones
in the formation or re-arrangement of transcription complexes in
vivo. Still, there has been some suggestive in vitro
evidence for direct chaperone involvement in the transcriptional
actions of steroid receptors. Greene and co-workers (52 53 ) observed
an Hsp70-dependent enhancement of ER-ERE binding in vitro,
although Hsp70 had no effect on ER-ERE binding in another study (54 ).
Hsp70 has also been observed in GR-glucocorticoid response
element (GRE) complexes (55 ).
As detailed in a recent review by DeFranco (56 ), chaperones are known
to influence the shuttling of steroid receptors between cytoplasmic and
nuclear compartments, the recycling of activated receptors, and the
subnuclear localization of receptors. Much remains unknown about the
specific roles and mechanisms for receptor-associated chaperones in the
distinctive pathways for import and export of steroid receptors through
nuclear pore complexes. It is known that Hsp90 can promote dissociation
of either ER (57 ) or GR (47 58 ) from DNA in vitro.
Furthermore, an increased concentration of nuclear Hsp90
downregulates GR transactivation of a reporter gene in
vivo (58 ), suggesting that intranuclear availability of Hsp90
might modulate expression of endogenous steroid-responsive genes.
Additional evidence for an Hsp90 role in GR recycling is provided by
the observation that geldanamycin, a specific Hsp90-binding drug (59 )
and inhibitor of steroid receptor functions in vivo
(60 61 62 63 64 65 ), can prevent release of hormone-withdrawn GR from
high-affinity chromatin sites (66 ). Thus, Hsp90, perhaps assisted by
partner chaperones, may be required for the efficient release of GR
from high-affinity chromatin sites after hormone dissociation.
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BAGging STEROID RECEPTORS
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Gehring and his colleagues identified a novel protein, originally
termed RAP46, that associates with activated forms of GR, ER, AR, and
thyroid hormone receptor (67 ). About the same time, a related protein
termed BAG-1 was found in association with Bcl-2 and shown to augment
Bcl-2-mediated suppression of apoptosis (68 ). It is now known (69 70 71 )
that RAP46 and BAG-1 are expressed from a common gene whose mRNA
harbors multiple alternative translation initiation codons that
generate human protein isoforms BAG-1S (
36 kDa), BAG-1M/RAP46/Hap
(
46 kDa), and BAG-1L (
50 kDa). BAG-1 isoforms have been
identified in complexes with several signaling proteins other than the
steroid receptors and Bcl-2. These include the retinoic acid receptor
(RAR) but not the retinoid X receptor (RXR) (72 ), receptors for hepatic
growth factor and platelet derived growth factor (73 ), and the serine
kinase Raf (74 ).
BAG-1 isoforms can affect nuclear receptor function, but in a manner
that so far has eluded easy explanation (see Fig. 2
). In an initial study on the effects of
BAG-1 isoforms on GR transactivation (75 ), BAG-1M overexpression
inhibited glucocorticoidinduced reporter gene activation and
apoptosis, and the GR hinge region was found to be necessary for BAG-1M
association. Later, it was shown that either BAG-1M or BAG-1L could
inhibit reporter gene activation, but the short isoform BAG-1S, which
associates with GR in a similar manner to the larger isoforms, failed
to inhibit GR-mediated transactivation (76 ). The loss of GR
transactivation was not due to a corresponding loss in GR hormone
binding ability, and BAG-1 isoforms caused no defects in GR-mediated
inhibition of AP-1 activity.

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Figure 2. Potential Effects of BAG-1 Isoforms on Steroid
Hormone Signaling
The various BAG-1 isoforms, perhaps in association with Hsp70, interact
with steroid receptors. Before hormone binding, BAG-1 isoforms can
potentially alter the dynamics of complex assembly and the
establishment of functional receptors. After hormone binding, BAG-1
isoforms can influence receptor-mediated transcriptional events at
hormone responsive genes.
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There are multiple inconsistencies in the observed effects of BAG-1
isoforms toward other nuclear receptors when compared with GR. First,
despite the close sequence similarity of GR to mineralocorticoid
receptor (MR), BAG-1 isoforms were unable to inhibit transcriptional
activation mediated by MR (76 ). In another case, BAG-1S, which failed
to inhibit GR transactivation, was found to interact with RAR and
inhibit DNA binding and transactivation by RAR:RXR heterodimers,
but no interaction with RXR or inhibition of transactivation by RXR
homodimers was observed (72 ). The final example of contrast is provided
by AR, the transactivation of which is potentiated by BAG-1L
but unaffected by either BAG-1M or BAG-1S (77 ).
The disparate influences of BAG-1 isoforms toward steroid receptors may
relate in some ways to the direct binding of BAG-1 isoforms to Hsp70, a
major receptor-associated chaperone. BAG-1 isoforms compete with Hip
for binding the ATPase domain of Hsp70 (78 79 ), and the presence of
BAG-1 generally inhibits Hsp70-mediated protein refolding activity
in vitro (80 81 82 ). BAG-1 isoforms also interfere with the
interaction between Hop and Hsp70 (83 ), even though Hop binds
independently to the Hsp70 C-terminal region (79 84 ). This likely
explains the observation that BAG-1S at elevated levels can inhibit
assembly and functional maturation of GR complexes (85 ). However, this
finding contrasts with the observation discussed above in which BAG-1S,
unlike the larger isoforms, did not inhibit glucocorticoid signaling in
cotransfected cells (76 ).
It is possible that BAG-1 isoform interactions with steroid receptors
and other signaling proteins are always mediated by Hsp70 such that
BAG-1-dependent functional changes result indirectly from changes in
the behavior of Hsp70 toward the target protein. Evidence for this
comes from observations that the C-terminal region common to all BAG-1
isoforms contains the Hsp70-binding site and is required for
association with signaling proteins (78 80 ). However, based on the
isoform-specific effects described above, this interpretation would
require that BAG-1 isoforms differ in their influence on Hsp70
function, a possibility that has not been adequately tested.
Alternatively, the isoforms could have direct and distinct functional
interactions that are not transmitted through Hsp70. For instance,
BAG-1S and BAG-1M exhibit a somewhat variable, but predominantly
cytoplasmic, localization in cells while BAG-1L is localized to the
nucleus and contains a putative nuclear localization signal in its
unique N-terminal region. In another case, Reeds group noted that a
C-terminal truncation of BAG-1L, which removes the Hsp70 binding site,
became a trans-dominant repressor of AR function (77 ). This
might suggest that the unique N terminus of BAG-1L has an important
interaction with AR transcriptional complexes that is unrelated to
Hsp70 function. On the other hand, downstream sequences shared with
other BAG-1 isoforms might have the potential for common
Hsp70-independent interactions that are only apparent with the
nuclear-localized BAG-1L mutant.
Both larger isoforms contain an 8-unit repeat of the sequence motif
[EEX4]truncated to only 2 units in BAG-1S.
Cato and colleagues (76 ) proposed that the larger repeat series could
provide a structural basis for the selective ability of large isoforms
to inhibit GR transactivation. Speculating on a possible mechanism, the
presence of multiple potential phosphorylation sites in this repeat was
noted, but little supporting evidence for differential phosphorylation
of BAG-1 was presented.
An alternative mechanism is suggested by the recent observation that
BAG-1M/RAP46/Hap can directly bind DNA, although in a rather
nonspecific manner (86 ). After addition of BAG-1M to a cell-free
transcription system containing HeLa nuclear extracts, RNA synthesis
was enhanced more than 10-fold. Overexpression of BAG-1M in transfected
cells also enhanced transcription, both from a generic chloramphenicol
acetyltransferase (CAT) reporter and from endogenous genes. In the
latter case, BAG-1M overexpression was found to efficiently block
transcriptional down-regulation of cellular mRNA production that
typically occurs in response to heat shock. The N-terminal sequence of
BAG-1M, which precedes the [EEX4] repeat region
by four amino acids, is MKKKTRRR. Truncation or alanine substitutions
of the basic triplets abrogated BAG-1M binding to DNA and enhancement
of cellular transcription events. (BAG-1L also contains the basic amino
acid triplets, but its DNA-binding ability was not examined.)
Conceivably, the colocalization of BAG-1M DNA binding activity with an
activated steroid receptor could influence transcription from
steroid-responsive genes. Looking to the future, there is likely to be
an increasing interest in BAG-1 isoforms and in BAG-related proteins.
There are at least four additional human genes whose protein products
contain a conserved BAG-like domain that confers Hsp70 binding (87 ),
but the functions of these other BAG family members have yet to be
explored.
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CONCLUDING COMMENTS
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Since their association with Hsp90 was first discovered some 20 yr
ago, steroid receptors have been a rich source for identifying
components, functional interrelationships, and complex pathways in the
molecular chaperone machinery. At the cellular level, steroid receptors
have illustrated, better than any other class of native chaperone
substrate, the diversity of cellular functions beyond simple protein
folding that molecular chaperones subserve. Many of the biochemical and
cellular mechanisms through which receptor-associated chaperones are
acting remain elusive, but these should become better understood in the
near future. With that understanding should also come opportunities to
expand the ways in which steroid and other chaperone-dependent
signaling pathways can be manipulated for therapeutic ends.
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ACKNOWLEDGMENTS
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Address requests for reprints to: David F. Smith, Johnson
Research Building, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259.
E-mail: smith.david26@mayo.edu.
Research efforts in the authors laboratory are supported by NIH
Grants DK-44923 and DK-48218.
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