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Molecular Endocrinology 14 (7):939
Copyright © 2000 by The Endocrine Society

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


   INTRODUCTION
TOP
 INTRODUCTION
ASSEMBLY OF STEROID RECEPTOR...
 MONKEY BUSINESS
 AFTER HORMONE BINDS
 BAGging STEROID RECEPTORS
 CONCLUDING COMMENTS
 REFERENCES
 
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 proteins—diverse representatives from multiple signal transduction pathways—that 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.


   ASSEMBLY OF STEROID RECEPTOR-CHAPERONE COMPLEXES: THE BASICS
TOP
 INTRODUCTION
 ASSEMBLY OF STEROID RECEPTOR...
MONKEY BUSINESS
 AFTER HORMONE BINDS
 BAGging STEROID RECEPTORS
 CONCLUDING COMMENTS
 REFERENCES
 
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 Pratt’s 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.


   MONKEY BUSINESS
TOP
 INTRODUCTION
 ASSEMBLY OF STEROID RECEPTOR...
 MONKEY BUSINESS
AFTER HORMONE BINDS
 BAGging STEROID RECEPTORS
 CONCLUDING COMMENTS
 REFERENCES
 
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 FKBP51’s 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 complexes—a combination of conditions that promote cortisol resistance.

Lending a more general relevance to FKBP51’s 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. 1Go. 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 GR’s affinity for hormone (bottom panel).

 

   AFTER HORMONE BINDS
TOP
 INTRODUCTION
 ASSEMBLY OF STEROID RECEPTOR...
 MONKEY BUSINESS
 AFTER HORMONE BINDS
BAGging STEROID RECEPTORS
 CONCLUDING COMMENTS
 REFERENCES
 
A common functional basis for steroid receptor-chaperone interactions has been the establishment and maintenance of the receptor’s 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 gene’s 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.


   BAGging STEROID RECEPTORS
TOP
 INTRODUCTION
 ASSEMBLY OF STEROID RECEPTOR...
 MONKEY BUSINESS
 AFTER HORMONE BINDS
 BAGging STEROID RECEPTORS
CONCLUDING COMMENTS
 REFERENCES
 
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. 2Go). 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.

 
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, Reed’s 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.


   CONCLUDING COMMENTS
TOP
 INTRODUCTION
 ASSEMBLY OF STEROID RECEPTOR...
 MONKEY BUSINESS
 AFTER HORMONE BINDS
 BAGging STEROID RECEPTORS
 CONCLUDING COMMENTS
REFERENCES
 
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.


   ACKNOWLEDGMENTS
 
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.


   REFERENCES
TOP
 INTRODUCTION
 ASSEMBLY OF STEROID RECEPTOR...
 MONKEY BUSINESS
 AFTER HORMONE BINDS
 BAGging STEROID RECEPTORS
 CONCLUDING COMMENTS
 REFERENCES
 

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