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Cell, Vol. 83, 851-857, December 15, 1995, Copyright 0 1995 by Cell Press

Steroid Hormone Receptors: Many Actors in Search of a Plot

Review

Miguel Beato,’ Peter Herrlich,t and Giinther Schlitz* *Institut ftir Molekularbiologie und Tumorforschung Philipps-Universitat Marburg Emil-Mannkopff-Strasse 2 D-35037 Marburg Federal Republic of Germany tForschungszentrum Karlsruhe lnstitut fiir Genetik D-76021 Karlsruhe Federal Republic of Germany *Deutsches Krebsforschungszentrum Im Neuenheimer Feld 280 D-691 20 Heidelberg Federal Republic of Germany

It tookalmost aquarterof acenturyfrom the earliest indica- tion that steroid hormones play a role in transcriptional control, triggered by the observation by Ulrich Clever of ecdysoneinduced giant chromosome puffs, and from the earliest detection of steroid hormone receptors (SHRs) to the cloning of their genes (reviewed by Evans, 1988). Although availability of the first SHR cDNA clones 10 years ago triggered the isolation of the now huge superfamily of nuclear receptors by homology screening with the DNA- binding domain (DBD) (Mangelsdorf and Evans, 1995 [this issue of Cell]; Thummel, 1995 [this issue of CeW]), the vertebrate SHRs have remained a distinct class that are different in several respects from all other nuclear receptors.

Prologue: The Main Actors SHRs exert their influence in embryonic development and adult homeostasis as hormone-activated transcriptional regulators. Their modular structure, consisting of a DBD, nuclear localization signals, a ligand-binding domain (LBD), and several transcriptional activation functions (AFs) (Figure l), is conserved with other members of the nuclear receptor family. Unique to the SHRs is their ability upon activation to bind to palindromic DNA sequences, called hormone response elements (HREs) (Figure l), ex- clusively as homodimers, at least in vivo. The receptors for glucocorticoids, mineralocorticoids, progesterone, and androgens recognize the same DNA sequence (AGAACA as half-site) that creates a specificity problem to be dis- cussed later, while the estrogen receptor recognizes AGG- TCA, identical with the half-site used by the nonsteroid nuclear receptors. Mutant data, nuclear magnetic reso- nance studies, and X-ray analyses of DBDlHRE cocrystals of glucocorticoid and estrogen receptors have shown that half-sites are distinguished by several amino acids (origi- nally named the P box by Umesono and Evans, 1989) of a recognition helix that is coordinated by a zinc-binding motif and makes base-specific contacts within the major groove. A second zinc atom organizes both an a helix, which is oriented alongside the axis of the DNA, and the D box, responsible, at least in part, for specific homodimer-

ization (Figure 1; reviewed by Glass, 1994). After binding to DNA, the receptor is thought to interact with components of the basal transcriptional machinery and with sequence-specific transcription factors. Although a number of such interactions have been described, the actual mechanism of steroid hormone action is still far from being understood. We know many actors, but we do not know the plot. The only certainty is that there are many more actors than expected and that the plot they are involved in is neither simple nor unique. In reviewing the wealth of recent reports on SHRs, we will describe various levels of regulation, focusing on a few well-characterized examples of hormonal induction and repression and on the insights gained by targeted disruption of the genes for SHRs.

The Curtain Rises: The Unliganded SHR Complex In contrast with other nuclear receptors, all unliganded SHRs are associated with a large multiprotein complex of chaperones, including Hsp90 and the immunophilin Hsp56, which maintains the receptors in an inactive but ligand-friendly conformation (reviewed by Pratt, 1993). SHRs introduced into yeast can be activated upon ligand addition. Data obtained in mutant yeast strains suggest that the chaperoning proteins play an active role in keeping SHRs functional. In yeast strains expressing the glucocorticoid receptor, disruption of the Hsp90 homologs does not lead to constitutive activation of the receptor but rather to a significant impairment of hormone induction (Bohen and Yamamoto, 1993). Chaperones in addition to Hsp90 are required for SHR function, as suggested by mutants of the yeast dnaJ homolog YDJl , which also associates with the unliganded SHR complex. In contrast with mutants found in hsp90, one ydil allele generates constitu- tively active estrogen and glucocorticoid receptors (Cap- Ian et al., 1995; Kimura et al., 1995).

Other Members of the Cast: Basal Transcription Factors and Coactivators To regulate transcription, liganded SHRs must talk to the transcription initiation complex. It is currently debated whether transcription initiation complexes assemble at the TATA box in an ordered stepwise fashion (TFIID > TFIIB > RNA polymerase II + TFIIF > TFIIE > TFIIH) or are recruited as preformed complexes. Such preformed holoenzyme complexes, containing RNA polymerase II and all relevant general transcription factors along with several additional polypeptides, exist in yeast (Kim et al., 1994; Koleske and Young, 1994) and in higher eukaryotes (Ossi- pow et al., 1995).

SHRs have been shown to interact in vitro directly with components of the transcription initiation complex (reviewed by Tsai and O’Malley, 1994), but the physiological significance of these interactions remains unclear. There have also been indications for the existence of coactivators that would act as bridging factors between SHRs and the transcription initiation complex. A number of such intermediary factors that interact with AF2 at the C-terminus

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-’ - - -7 oeo /

------.-..,‘i ___..._ ___1... -‘-iso .-.AFPj Figure 1. Domain Structure of SHRs

..~- . . ..__.... ._

“xET icOiC;iVatorsl 1

The glucocorticoid receptor is taken as a model tovisualize general features: thecore transactivation domains AF1 (also called ~1) (which is

RIP 140 TIF-I /

hormone independent) and AF2 (which is hor- SUG-1 : mone dependent). AF2, to which the putative

..-__-- coactivators introduced in the text bind, is lo-

v

cated in the C-terminal portion of helix 11 of the LBD. The backbone drawing is derived from the crystal structure of the RXRa LBD (Bourguet et al., 1995), possibly resembling those of SHRs. The DBD of the glucocorticoid receptor (schematic derived from Glass, 1994) is assembled as a dimer on the palindromic HRE. The organization by the zinc-binding mo- tifs is made visible by the expanded drawing. @stands for hydrophobic amino acid in the putative AF2 consensus sequence.

of SHR (Figure 1) in an agonist-dependent fashion have been identified (Halachmi et al., 1994). One of them, RIP140, binds only to transcriptionally active variants of estrogen receptor and appears to interact with estrogen receptor in vivo (CavaiWs et al., 1995). Another protein, TlFl , interacts with retinoid X receptor y (RX@) and estrogen and progesterone receptors and belongs to a group

of so-called RING proteins (Le Douarin et al., 1995). The RING family includes PML, the transcription factor to which retinoic acid receptor a (RARa) is fused in acute promyelocytic leukemia, which itself enhances transactivation by progesterone receptor (Guiochon-Mantel et al., 1995), and the estrogen-responsive finger protein Efp (ln- oue et al., 1993). As estrogens also induce expression of the progesterone receptor, complex cascades of hormone regulation as in insects (Thummel, 1995) may also exist in mammals.

Another AF2-binding protein, SUGl, interacts with several nuclear receptors, including SHRs, and is a compo- nent of the RNA polymerase II holoenzyme (see Mangelsdorf and Evans, 1995). Therefore, SUGl could be contacted by SHR for recruiting the holoenzyme. Addi- tional SHR-interacting proteins have been identified (Oiiate et al., 1995), and it is also possible that the action of coactivators presupposses the ligand-dependent displacement of corepressors, as described for other nuclear receptors (reviewed by Mangelsdorf and Evans, 1995).

The emerging picture outlines several possible interactions of SHRs with components of the initiation complex but also with a number of intermediary factors. The latter probably form a large family with differential affinities for various SHRs. Sorting out the meaning of these interactions is a challenge for the near future.

Cross-Talk: To Be or Not to Be-Active SHRs are not only capable of stimulating gene activity, but are also competent transcriptional repressors. Theo- retically, transcriptional repression occurs by competition for the DNA-binding site (see examples in Thummel, 1995), by competition for common mediators to the transcription initiation complex, or by sequestration of the transcription factors into inactive forms. The last of these possible mechanisms is exemplified in the transcrip0onal

interference of nuclear receptors with two groups of transcription factorsof particular physiologic importance, AP-1 and NF-~6.

Inhibition of AP-l-dependent genes by nuclear recap- tors is transcriptional and rapid, does not require protein synthesis, and can be traced to an interaction of AP-1 with nuclear receptors (reviewed by Schijle and Evans, 1991; Saatcioglu et al., 1994; Herrlich and Ponta, 1994). The relationship is mutual in that elevated expression of AP-1 subunits or their activation in response to growth factors or phorbol ester inhibits HRE promoters. As an important feature of this mutual inhibition, the interfering factor does not seem to contact DNA, and the repressed factor remains DNA bound. No major change in genomic dimethyl sulfate footprint has been detected at the AP-1 site of the glucocorticoid-repressed endogenous collagenase promoter (Kiinig et al., 1992) nor over the HRE of the glucocorticoid-induced and phorbol ester-repressed (and thus probably AP-1 -repressed) tyrosine aminotransferase gene (Reik et al., 1994). The mutual interference and the stoichi- ometry suggested from cotransfection experiments argue for direct interaction between SHR and AP-1. Direct interaction occurs between in vitro translated glucocorticoid receptor and Jun (reviewed by Yamamoto et al., 1993; Saatcioglu et al., 1994; Herrlich and Ponta, 1994), but there is yet no convincing proof of its in vivo significance.

The AP-1 inhibitory property of SHRs is clearly distinct from their transactivating function. It is ligand dependent but appears to occur at lower ligand concentration than transactivation (Jonat et al., 1990; see references in Saat- cioglu et al., 1994). Several antiglucocorticoids, antiprogestins, and antiandrogens interfere with DNA binding (e.g., Becker et al., 1986; Truss et al., 1994; Heck et al., 1994), but induce transrepression (Heck et al., 1994), sug- gesting that different ligands can bring about substantially different SHR conformations. Repressing and activating properties of SHRs are further discriminated by receptor mutations (Heck et al., 1994; Helmberg et al., 1995). In particular, mutants that cannot bind to DNA, mutants with defective AFs, and D box mutants that (in case of the glucocorticoid receptor, with no known other dimerization interphase) cannot dimerize repress AP-1 -dependent promoters perfectly well, presumably as monomers. Mutual

Review: Steroid Hormone Receptors 853

repression requires N-terminal sequences of SHRs and the basic-leucine zipper region of Jun (see also discussion in Saatcioglu et al., 1994). Many of these conclusions rely on cotransfection experiments and therefore need to be taken with caution.

How can bona fide transcription factors be converted into repressors? An interesting hint has come from the observation that glucocorticoid receptor and Jun homodimers synergize, while glucocorticoid receptor represses Fos-Jun heterodimers (Yamamoto et al., 1993; Teurich and Angel, 1995), which suggests conformational changes by protein-protein interaction as basis for altered activity. An influence of DNA on SHR conformation has been pos- tulated (reviewed by Yamamoto et al., 1993; Lefstin et al., 1994). While well known for RXR heterodimers (Mangels- dorf et al., 1991; Saatcioglu et al., 1994), data for glucocorticoid receptor modulation by so-called negative HREsand composite elements are not persuasive. Binding of glucocorticoid receptor to such elements has yet only been shown in vitro (but not in vivo, e.g., by genomic footprinting) and often requires high concentration of recombi- nant receptor.

It therefore appears that, as a common principle, SHRs can exist in a transactivating or a repressing conformation in which the activation domains are disguised (Figure 2). Interacting proteins and ligands convert one form into the other. Protein-protein interaction can be mutual, and not only the synergy but also the inhibition occur with only one factor bound to DNA. It is not yet clear whether these rules of mutual interactions as described for SHRs and AP-1 can be applied to other transcription factors such as GATAl and Spil and to putative cell type-specific factors modulating SHR transcription factor cross-talk, all of which we have not covered here.

The interference of SHRs with the other important factor of the inflammatory response, NF-KB, has only recently been studied. Overexpression of ~65, one of the transcriptionally active subunits of NF-KB, and of glucocorlicoid receptor, as well as in vitro binding between p65 and receptors for either glucocorticoid, progesterone, or estrogen suggest a mutual interference mechanism as for AP-1 (Stein et al., 1993; Ray and Prefontaine, 1994; Stein and Yang, 1995; Caldenhoven et al., 1995; Scheinman et al., 1995a). In keeping with this notion, interleukin-2 expression by a leukemic cell line selected for glucocorticoid- inducible apoptosis is inhibited by a transactivation- defective glucocorticoid receptor mutant (Helmberg et al., 1995). The glucocorticoid receptor seems to block NF-KB DNA binding as measured by bandshifts in vitro. Inhibition by glucocorticoid of promoters containing NF-KB sites could, on the other hand, be explained by the recent finding of rapid induction of lKBa synthesis in response to hormone (Scheinman et al., 1995b; Auphan et al., 1995). IKB traps NF-KB in the cytoplasm, and its increased synthesis may revert NF-KB binding to promoters. These interesting findings reopen the debate on the antiinflammatory action and induction of apoptosis by SHRs. Is the balance between apoptosis and survival regulators disturbed by the interference with a survival pathway or by induction of a suicide gene? Although indications exist (Auphan et

B glucocorticoid receptor

C glucocorticoid CXf2pt”r

Figure 2. Synergizing and Repressing Interactionsof SHRs with Other Transcription Factors

In the well-known assembly with individual DNA elements in the same promoter (A), transcription factors in their transactivating (circle) conformation interact with coactivators and, in an unknown fashion, bun- dle their stimuli to the transcriptional initiation complex. Two different transcription factors can also act from one promoter element, envis- aged here as synergy (6) of, e.g., a Jun homodimer at an AP-I-binding site with the glucocorticoid receptor and as repression (C). The latter interaction needs to alter the conformation of the partners (shown as rectangles, concealing the activation domains). The glucocorticoid receptor may repress as a monomer (see text) and engage corepres- sion. Direct protein-protein interaction of the transcription factors, perhaps with participation of tissue-specific additional factors, determines the regulatory properties.

al., 1995; Berko-Flint et al., 1994), the relevance of negative regulation by SHRs in the intact organism awaits convincing demonstration, e.g., by appropriate rodent or human mutants.

Do the Actors Need a Revolving Stage?: Role for Chromatin The interaction between proteins and DNA and among SHRs, transcription factors, and the initiation complex has to cope with the structural organization of DNA in the nu- cleus. Genetic analysis has revealed a widespread involvement of chromatin structure in gene regulation. Transactivation by glucocorticoid receptor in yeast requires components of the SWllSNF complex (Yoshinaga et al., 1992), a set of pleiotropic transactivators that coun- teract repressing functions of chromatin and are therefore important for transcription of inducible genes (Winston and Carlson, 1992). In human cells lacking a homolog of SWl2, human Brm (hBrm), transactivation by glucocorticoid receptor is weak and can be selectively enhanced by expression of hBrm (Muchardt and Yaniv, 1993). Like SW12 in yeast, hBrm is part of a large multiprotein complex that mediates ATP-dependent disruption of a nucleosome and

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enables binding of GAL-linked transactivators to GALC binding sites in nucleosomes (Kwon et al., 1994). Asecond human homolog, BRGl, is a nuclear protein that can re- store glucocorticoid receptor-dependent transcription in yeast strains lacking SW12 (Khavari et al., 1993). BRGl binds specifically the retinoblastoma gene product Rb, and Rb up-regulates glucocorticoid receptor-mediated transactivation only in the presence of hBrm (Singh et al., 1995). These results document the link between SHR and the complex cellular machinery involved in chromatin dy- namics and cell cycle control.

One of the Scenes: The Mouse Mammary Tumor Virus Promoter The mouse mammary tumor virus (MMTV) promoter is a well-documented example of transcriptional control by steroid hormones. The SHRs bind to several HREs and facilitate the interaction of other transcription factors, including nuclear factor 1 (NFl) and the octamer transcription factor OTFl , with the MMTV promoter (reviewed by Truss and Beato, 1993). Nucleosomes are nonrandomly distributed on the MMTV promoter (Richard-Foy and Hager, 1987), though a more heterogeneous distribution of nucleosome positions is found by formaldehyde fixation (Fragoso et al., 1995). One dominant nucleosome phase found both in mammalian cells and in yeast carrying an MMTV promoter permits SHR binding to HREs while pre- cluding binding of NFI (Truss et al., 1995; Chavez et al., 1995). This difference probably reflects the different ways in which various proteins recognize their cognate DNA sites (Figure 3). Such data imply that DNA contains conformational or topological information that is implemented in chromatin and modulates the accessibility to &-acting elements.

Hormone induction was believed to cause a displacement of the nucleosome over the HREs, thus allowing free access of NFl to its binding site and transcriptional activation (Richard-Foyand Hager, 1987). However, genomic footprinting of the chromosomal MMTV promoter shows that hormone induction does not lead to displacement, but rather to a rearrangement of the nucleosome that enables simultaneous binding of receptors, NFl and OTFl (Truss et al., 1995). Since these factors cannot bind simultaneously to the MMTV promoter on free DNA, the organization in chromatin may beaprerequisiteforoptimal induction of the MMTV promoter. One attractive possibility is that the hormone-induced nucleosomal change may be related to the recently observed receptor-mediated recruit- ment of the SWllSNF complex or of other chromatin remodeling factors (Figure 4).

Knockout of the Players Provides New Insights into Old Problems Even though a wealth of information on steroid action is available, the generation of mice with mutations in the major vertebrate SHRs by homologous recombination in embryonic stem cells has generated new and often unexpected insights. With the exception of the androgen insensitivity syndrome (reviewed by McPhaul et al., 1993) and

Nucleosome Free DNA

Orientation 1 Orientation 2

A

Figure 3. Influence of Nucleosomal Phase on Protein-DNA Interac- tions

(A) Proteins, such as NFI or OTFl, that interact with over half the helix circumference (stippled) cannot bind to their nucleosomally organized cognate sites, irrespective of the rotational orientation of the major groove. (8) Proteins, like SHRs, which contact only a narrow sector of the helix (around 100°), would bind if the major groove were exposed (orientation l), but not if it pointed to the histone octamer (orientation 2) (Li and Wrange, 1995).

the recent description of a male with a mutation in the estrogen receptor gene (Smith et al., 1994), no complete loss-of-function mutation in other human or murine SHR genes has been described that suggested that complete loss of any one of these receptors might lead to embryonic lethality. This suspicion has been substantiated for null mutations in mice of the glucocorticoid receptor, but not for the sex steroid receptors. Glucocorticoid Receptor Disruption of the glucocorticoid receptor gene is expected to interfere with many physiological processes, such as regulation of carbohydrate, protein and lipid metabolism, and modulation of immune and central nervous system (CNS) responses. Unexpectedly, the analysis of the glucocorticoid receptor-negative mice revealed that the receptor is also required for maturation of several organ sys- tems, e.g., lung and adrenal gland (Cole et al., 1995), perhaps also explaining why so far only partial loss-of- function mutations have been observed in humans. Most of the glucocorticoid receptor-deficient mice die shortly after birth owing to respiratory failure caused by lack of inflation of the lungs, likely resulting from lowered produc- tion of surfactants and from deficiency of a glucocorticoid- inducible sodium channel. The adrenals of mutant mice lack adrenergic chromaffine cells from day 13 of embryonic development. These cells are derived from a bipoten- tial neural crest cell population that, depending on environ-


SHR

+

SWVSNF

Figure 4. Model for Remodeling of Chromatin by SHR

SHR could remodel chromatin by recruiting the SWILSNF complex or other factors that, e.g., catalyze the displacement of histone H2A/ histone H2B dimers (Cbt6 et al., 1994).

mental cues, gives rise to chromaffine cells in the presence of glucocorticoid or to sympathetic neurons in the presence of nerve growth factor. Sex Steroid Receptors Two general conclusions can be drawn from the analyses of mice lacking a functional receptor for either estrogens, progesterone, or testosterone: lack of these receptors is not lethal, and the balanced sex ratio observed suggests that their absence does not affect the processes leading to sex determination. Ablation implicates the progesterone receptor and its ligand in many functions other than pregnancy (Lydon et al., 1995). Mice without progesterone receptor develop normally, but female homozygous mice are infertile owing to abnormalities in the reproduction system. In addition to pregnancy, ovulation, luteinization, and mammary gland development are impaired.

In contrast with the plethora of spontaneous human and rodent androgen receptor mutations, the lack of a mutation of the estrogen receptor suggested its involvement in some vital function. Therefore, it was surprising that mice without estrogen receptor are viable, even though they are severely compromised in reproductive functions (Lu- bahn et al., 1993). Mice of both sexes are infertile, an unexpected finding for males devoid of estrogen receptor. The testes are smaller, and the seminiferous tubules are structurally altered. Apparently, the estrogen receptor has a direct role in the spermatogenic process. In the female, follicular development is impaired and hemorrhagic cystic ovaries develop, possibly owing to excessive gonadotro- pin stimulation. Since one of the well-established targets of estrogen action is the progesterone receptor gene, the relative contributions of either receptor remain to be de- fined.

Abnormalities of male phenotypic development due to

an altered androgen receptor have been frequently observed in several species, including humans, rats, and mice. The wide phenotypic spectrum observed in patients with the androgen insensitivity syndrome will be of great value for understanding the detailed structure/function relationship of this receptor in vivo (McPhaul et al., 1993). Recently, amplificatiotl of the androgen receptor locus has been observed in hormone-insensitive prostate cancers (Visakorpi et al., 1995), which is likely to be of importance in prostate cancer development from a hormone-sensitive to a hormone-refractory state.

Perspectives: The Curtain Does Not Fall The availability of SHR knockouts and of SHR mutant mice to come will help in numerous open questions touched upon in this review, e.g., the role of glucocorticoid receptor in T cell formation and apoptosis and in the control of the acute phase response, the in vivo significance of activating and repressing SHR functions, the functional significance of SHR variants produced from nested primers or by alter- native splicing (e.g., the 0 isoform of the glucocorticoid receptor and the A form of progesterone receptor; see also similar variants of nonsteroid receptors in Thummel, 1995), SHR function in the CNS, and the role of estrogens in bone formation and osteoporosis and in the development of steroid hormone-dependent cancers. Receptor- deficient mice will also be a prerequisite for a critical analysis of putative nonsteroid receptor-mediated effects of gluco- and mineralocorticoids as well as of estradiol (Mani et al., 1994; Aronica et al., 1994).

SHRs utilize the same or highly related DNA-binding sites. This prompts the following question: how does an ubiquitous hormonal signal become interpreted in a tem- porally and spatially restricted manner? Recent investiga-

tions have revealed several mechanisms through which selectivity might be achieved. One obvious mechanism to achieve steroid-specific gene activation is differential expression of the receptor itself. Indeed, expression of the progesterone receptor in hepatoma cells, where it is normally not expressed, has led to activation of glucocorticoid-dependent genes. Selective steroid transport has been suggested from studies in yeast (Kralli et al., 1995). Selective inactivation of hormone in tissues, as seen for glucocorticoids in the collecting ducts of the kidneys, is another important mechanism to guarantee selectivity (Funder, 1993).

A clinically very important open question concerns the mechanism of mitogenic effects of steroid hormones, in particular the proliferative actions of estrogens and progesterone in uterine and mammary tissues. Ovarian hormones up-regulate the transcription of immediate-early genes such as c-fos, c-jun, and cyclin Dl . Targeted disruption of the cyclin Dl gene prevents proliferation of the mammary gland during pregnancy (Sicinski et al., 1995) and yields a phenotype similar to that observed in mice deprived of progesterone receptor (Lydon et al., 1995). The pathway leading to cyclin Dl activation is under inves- tigation and may be a target area for cancer therapy.

This summary of recent developments shows that con-

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trol of gene expression by steroid hormones is far more complex than was apparent at the time when the genes for SHRs were isolated. With more and more players getting on stage, we realize not only this complexity but also the persuasive role steroid hormones play in a vast number of physiologic and pathologic processes.

Acknowledgments

We are grateful to numerous colleagues who sent their published and unpublished data. We apologize that because of limited space not all work could be included, and many are referred to through review articles. We thank our colleagues who contributed criticisms and information: Peter Angel, Andrew Cato, Martin GBttlicher, Jijrg Klug, Rein- hard Ltihrmann, Paula Monaghan, Rolf MOller, Mark Nichols, Francis Stewart, Guntram Suske, and MathiasTruss. This workwas supported by the Deutsche Forschungsgemeinschaft.

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steroid hormone receptors: review many actors in search of ...€¦ · tants found in hsp90, one...

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