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Contents lists available at ScienceDirect
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Historical overview of nuclear receptors
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Jan-Ake Gustafsson a,b, *
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a b
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
A R T I C L E I N F O
Article history: Received 10 December 2014 Received in revised form 2 March 2015 Accepted 16 March 2015 Available online xxx
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This chapter aims to outline some important events in the development of the nuclear receptor field. Needless to say, it is impossible to mention everyone who has contributed to the fascinating progress of this extremely important research area but (as many others have done before) I will rather give a historical overview from my own perspective. It occurs to me that one way to start this little review is to describe some of the highlights of the Nobel Symposium 1983 on “Steroid Hormone Receptors: Structure and Function”, held in Karlskoga (city where Alfred Nobel had lived), Sweden. Lectures and discussions were published in a special volume “Nobel Symposium No. 57”, edited by Hakan Eriksson (my first student) and me [1]. The meeting was inaugurated by the Swedish King and Queen and attended by most of the high-profile researchers in the nuclear receptor field at the time. The subjects discussed reflect quite well the state of the art and the prevailing ideas about where we were going. The mystery of how binding to ligand resulted in the ability of the receptor to bind to DNA was being addressed by biochemical characterization of the structure of steroid receptors. The purification of these proteins from tissues was then (and would be today) an intensely laborious job, which was complicated by the sensitivity of these proteins to proteolytic degradation. It has to be remembered that, at the time, steroid receptors had not yet been cloned so they had to be traced by labeling with tritiated ligands like dexamethasone, estradiol and 5a-dihydrotestosterone. Jean-Pierre Raynaud, then at Roussel-Uclaf in Paris, had led the development of non-metabolizable ligands like R 1881 for the androgen receptor and R 5020 for the progesterone receptor and this considerably facilitated the work with these receptors [2]. Our own group presented data on the structure of the glucocorticoid
* Correspondence address: University of Houston, Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, 3605 Cullen Blvd, SERC Bldg 545, 3rd Floor, Houston, TX 77204, United States. Tel.: +1 8328424749.
receptor (GR) with which we had been working since the early 1970’s. With limited proteolytic digestion we found that the receptor was composed of three distinct domains: the ligand-binding domain, the DNA-binding domain and the immunoreactive domain [3]. The full-length GR had a molecular weight of 94 K; the combined DNA- and ligand-binding domains 39 K and the ligand-binding domain 19 K. The immunoreactive domain (later shown to be the N-terminal domain) was discovered using mono- and polyclonal anti-GR antibodies developed in our laboratory following our purification of the GR to homogeneity [4]. Interestingly, we found the N-terminal domain to be more sensitive to proteolytic digestion than the other two domains. Later on, the reason for the sensitivity of the N-terminal domain became clear: it is very unstructured and accessible to proteases. The three-domain structure of GR was subsequently shown to be characteristic for all nuclear receptors. Other contributions to the session on steroid receptor structure were from the laboratories of Bert O'Malley and Etienne-Emile Baulieu. The O'Malley laboratory described two forms of the chick oviduct progesterone receptor (PR), A and B; the smaller A receptor bound more strongly to DNA than the B form. Later research has established that both the B form and the A form are encoded by the same gene with the B form being the longer protein. Baulieu reported on a “non-transformed”, “non-activated”, “8S” form of PR that was converted to a “4S” form under high salt condition. The “8S” form contained both liganded PR and a 90 K non-progesterone-binding protein, later shown to be a heat shock protein (hsp90). A few years later the nature of the 8S and 4S forms of various hormone receptors was clarified; hsp90 was shown by other labs, including ours, to bind to the GR ligand-binding domain as a dimer. The binding stabilized the receptor in a ligand-accepting conformation. Upon binding to ligand, the hsp90 dissociated from the receptor, enabling it to bind to DNA [5]. Specific DNA-binding of steroid receptors was the theme of yet another session of the 1983 Nobel Symposium. This aspect of
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Please cite this article in press as: J.-A. Gustafsson, Historical overview of nuclear receptors, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi. org/10.1016/j.jsbmb.2015.03.004
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steroid receptor biology is, of course, extremely important. During the 1970’s many groups had found that steroid receptors interacted nonspecifically with DNA but this did not explain how the receptors could turn on the transcription of specific genes. Farhang Payvar from Keith Yamamoto's group and Orjan Wrange from our group used DNA purified from the mammary tumor virus (MTV) and showed that there were specific sites on DNA with which purified GR interacted [6,7]. Five specific binding sites, two of which located in the MTV LTR regions, were found. The site in the 50 LTR was shown to confer glucocorticoid responsiveness to downstream genes and was called glucocorticoid response element (GRE) [8]. These findings marked the entrance of steroid receptor research into a more molecular era. The demonstration of specific binding of GR to GRE was made possible by the combined efforts of two research groups, ours with highly purified, homogeneous receptor, and Yamamoto’s with an isolated, GR-sensitive gene, MTV. Subsequent research showed that GR binds to GRE as a homodimer. There was also a session in the symposium on the physiology of steroid receptors. This session was introduced by Elwood Jensen, celebrated for his discovery at the end of the 1950’s of the estrogen receptor (ER) alpha, which Jensen called “estrophilin”. In his Nobel Symposium lecture 1983, he described his development of monoclonal antibodies against the receptor and the use of these reagents to measure ERalpha in human breast cancer as a means to predict hormone responsiveness. On a similar theme, Marc Lippman described ERalpha in MCF-7 breast cancer cells and how its ligand estradiol-17beta stimulated proliferation of these cells. MCF-7 cells later became a generally used model system to study tumorigenic properties of ERalpha. Other well-known researchers who gave lectures during the 1983 Symposium were Brad Thompson (GR in steroid-sensitive and – resistant leukemic cells), Edwin Milgrom (progesterone receptor), Donald Coffey (nuclear matrix), Robert Schimke (mechanism of drug resistance), Arun Roy (alpha2-urinary globulin), Shutsung Liao (androgen receptor), Olli Janne (androgen receptor) and Anthony Norman (vitamin D receptor). Overall, the 1983 Nobel Symposium shows how advanced the nuclear receptor field was already “BC” (before cloning). The basic, three-domain structure (steroid binding-, DNA-binding and “immunoreactive” (later called the N-terminal domain) domains) had been discovered. Specific binding of GR to GREs had been found. After GREs had been reported, a series of confirmatory studies with other nuclear receptors followed, showing that indeed all steroid hormone responsive elements were steroid-activated enhancers of gene transcription. With the access to poly- and mono-clonal antibodies to steroid receptors it became possible to clone these proteins. Since the mRNAs of nuclear receptors are expressed at extremely low levels in tissues, it took some time with the available techniques to carry out this task. The first breakthrough resulted from the continued collaboration between the groups of Yamamoto and myself and was published in 1984 [9]. In a Nature paper we described the cloning of a part of the GR cDNA and used this to perform Northern blots of GR mRNA from several lymphoma cell lines with aberrant glucocorticoid signaling. This was the first published study of nuclear receptor mRNAs. One year later, Evans’ group published the full length GR cDNA in the same journal and confirmed the three-domain structure of nuclear receptors [10]. Our own full length GR cDNA publication followed a few months later in Cell [11]. The DNA-binding domain turned out to consist of two zinc fingers. Because the two zinc finger domain was conserved in all nuclear receptors, the race was on to clone all members of this family by cross hybridization based on the nucleotide sequence of GR cDNA. Several groups described new proteins with the typical
three-domain structure, showing that the nuclear receptor family contained more members than just the steroid hormone receptors. Some of these new proteins had a bona fide ligand binding domain but without a well defined ligand, at least initially. They were called “orphan receptors” and are the main subject of the present volume. The first examples were the estrogen related receptors (alpha, beta and gamma) reported by the Evans group [12]. Whether or not there are physiological ligands for these proteins is still the subject of discussion. In addition to the orphan receptors other new members of the nuclear receptor family were also cloned. Some of these were receptors that were already well known, such as the thyroid hormone receptor (TR alpha and beta; Vennstrom and Evans) [13,14] and the all-trans retinoic acid receptor (RAR alpha, beta and gamma; Chambon and Evans) [15,16]. A relative to RAR, H-2RIIBP, was cloned soon afterwards by Hamada et al. [17]; it was later renamed retinoid X receptor (RXR) beta [18] and Zhang et al. [19] and Marks et al. [20] showed the importance of this receptor in nuclear receptor signaling as it is the heterodimeric partner of orphan and other nuclear receptors. The true nature of the physiological ligand of RXR is still a matter of some debate but this function has been ascribed to 9-cis retinoic acid [21,22]. A prerequisite for a full understanding of the mechanism of action of nuclear receptors is knowledge of their 3-D structure. It has proven to be quite difficult to reach this goal. Until the cloning of nuclear receptor genes, high-resolution structural studies could not have happened because of the difficulties of purifying to homogeneity receptor quantities necessary for such studies. The development of good expression systems for expression of the cloned cDNAs provided structural biochemists with high quality purified receptors in large quantities. The first domain structure to be solved was the DNA-binding domain (DBD) of GR. This was achieved with NMR and was carried out in a collaboration between the laboratories of Härd et al. [23]. Important parts of the structure were two a-helices, one of which entered the major groove of DNA with the second a-helix perpendicular to the first. Later studies of the 3-D structures of other nuclear receptor DBD:s showed that all of them shared the same overall structure as the GR DBD. The ligand-binding domain (LBD) 3-D structure was first solved for the TR (Wagner et al.) [24] and RAR (Renaud et al.) [25]. When compared to a previously published structure of non-liganded RXR [26], it was suggested that when the ligand binds to the LBD, helix 12 folds over the ligand, constituting a roof over the ligand-binding cavity (“mouse trap model”). This concept still needs to be confirmed by further studies. In a later investigation, Hubbard, Carlquist and Gustafsson compared the 3-D structures of ERa bound to an agonist (estradiol-17b) or an antagonist (raloxifene) and concluded that the antagonist, through its long side arm, displaces helix 12 so that it precludes the binding of a co-activator [27]. This mechanism of action of ER antagonists was later confirmed by others. High-resolution quaternary multi-domain structures of nuclear receptors have been extremely difficult to obtain. At least part of the problem is attributable to the non-structured nature of the Nterminal domain (NTD) making it very sensitive to proteolytic degradation and difficult to crystallize. Over the recent several years only three such structures have been obtained, PPARa/RXRa heterodimer and HNF4 homodimer (Chandra et al.) [28,29] and LXRb/RXRa heterodimer (Lou et al.) [30]. In all three cases the crystal structures contained the LBD, DBD, part of the NTD, ligand (except for HNF4), coactivator peptide and DNA (DR1 for PPARa/ RXRa and HNF4, DR4 for LXRb/RXRa). In case of the DR1 bound complexes the domains appear quite tightly packed whereas the DR4 bound heterodimer shows a high degree of flexibility between the domains. These differences will help in the understanding of why different heterodimers bind to DR1, 2, 3 and 4, respectively.
Please cite this article in press as: J.-A. Gustafsson, Historical overview of nuclear receptors, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi. org/10.1016/j.jsbmb.2015.03.004
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Several reviews have been written about nuclear receptor co-activators and co-repressors. Therefore, although very important, these aspects of nuclear receptor mechanisms of action will not be treated further here. However, this review will touch upon the theme of physiological and pathophysiological aspects of nuclear receptors. Over the recent two decades much attention has been paid to the involvement of nuclear receptors in reproduction, metabolism (obesity, diabetes), cancer and CNS function, including stress [31]. One of the initial events in this development was the demonstration that one of the orphan receptors, PPARa, was activated by a whole range of fatty acids at micromolar concentrations [32]. This crucial result contrasted to previous findings that steroid hormones activate nuclear receptors at nanomolar levels. Furthermore, it demonstrated that important molecules in nutrition and metabolism could control the activity of nuclear receptors. Soon these findings were confirmed in several laboratories and it became apparent that the PPAR isoforms could bind a wide array of fatty acids and fatty acid metabolites. The previous concept of the narrow and high ligand specificity of nuclear receptors, like the steroid hormone receptors, thus had to be modified. Another nuclear receptor binding lipids and regulating lipid metabolism is Liver X Receptor (LXRalpha and LXRbeta), a misnomer since only LXRalpha is present in significant quantities in the liver. LXRbeta is ubiquitously expressed including in some non-hepatocyte liver cell types such as those that comprise the biliary tree [33]. The nature of the physiological ligand(s) of LXR is still not firmly established although oxygenated cholesterol metabolites appear to be good candidates [34]. However, other molecules of widely differing nature such as glucose and bile acids have also been claimed to be endogenous activators of LXR. The promiscuous nature of LXR ligands is reminiscent of that of the PPAR isoforms. It is tempting to speculate that these transcriptional regulators of lipid metabolism may be activated by tissue- and context-dependent ligands. A new area of great importance where LXRbeta seems very essential is the CNS. In adult mice this receptor is only expressed in microglia where it plays a role in the proper functioning of neurons in the substantia nigra. Deletion of LXRbeta results in Parkinsonism/ALS syndrome [35]. Furthermore, this receptor is essential for differentiation of radial glial cells to oligodendrocytes and thus for myelination of axons [36]. During development, LXRbeta is expressed in neuronal stem cells in the ventral midbrain and participates in the differentiation of these cells to dopamine containing neurons [37]. These findings indicate that LXRbeta might be a therapeutic target in multiple sclerosis and Parkinson’s disease. The discovery of a second estrogen receptor, ERbeta, was one of the most surprising events in the cloning of nuclear receptors [38]. Before this it had generally been assumed that “Jensen’s ER”, now renamed ERalpha, was the only ER. The multiple and sometimes opposing effects of estradiol all had to be explained in the context of a single receptor and all tissues which responded to estradiol but did not express this ER (lung and prostate included) were deemed to be indirect targets of estradiol. The ERbeta gene is localized on human chromosome 14, ERalpha on chromosome 6. In general terms, the two ERs often have a yin/yang relationship. For instance, ERalpha is pro-proliferative in the mammary gland whereas ERbeta is anti-proliferative. This particular characteristic of ERbeta makes it a possible therapeutic target in several cancers, e.g. breast, colon and prostate. The LBD:s of ERalpha and ERbeta, respectively, are different enough that it was possible for chemists to synthesize ERbeta specific agonists. Such compounds are now in clinical trials, not only against proliferative diseases but also against certain CNS ailments as schizophrenia since ERbeta is also expressed in several areas of the brain implicated in CNS diseases [39].
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In summary, the field of nuclear receptors has undergone an astounding evolution since Elwood Jensen’s discovery of ERalpha at the end of the 50’s. Nevertheless, important gaps in our knowledge remain to be addressed. High resolution quaternary structures of full length nuclear receptors interacting with full length co-activator and co-repressor proteins, if possible also with other components of the transcriptional machinery, are necessary for a more complete understanding of nuclear receptor action. The nature of the physiological ligands of nuclear receptors needs to be revisited and the traditional activators of these proteins must be complemented with novel alternatives. New knowledge of ligands of nuclear receptors will lead to better understanding of the role of these regulatory molecules in physiology and disease and therefore create novel therapeutic drug opportunities. A particularly exciting, evolving field is the gut microbiome, which has been called “a new endocrine organ” [40], continuously secreting bacterial metabolites and components with remarkable effects on the host’s homeostasis. Many orphan receptors still need to be de-orphanized and in this context, perturbation of the physiological effects of receptor-interacting endocrine disruptors, particularly in the fetal and neonatal periods, requires urgent attention. It should not be overlooked that many of these novel receptors are expressed in the central nervous system and they provide us with a new understanding of, and possibly novel targets for, the bane of our society, namely neurodegenerative disorders.
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This work has been supported by the Robert A. Welch Q7 Foundation (E-0004).
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Contents lists available at ScienceDirect
Journal of Steroid Biochemistry & Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb
1
Historical overview of nuclear receptors
2 Q1
Jan-Ake Gustafsson a,b, *
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a b
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
A R T I C L E I N F O
Article history: Received 10 December 2014 Received in revised form 2 March 2015 Accepted 16 March 2015 Available online xxx
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This chapter aims to outline some important events in the development of the nuclear receptor field. Needless to say, it is impossible to mention everyone who has contributed to the fascinating progress of this extremely important research area but (as many others have done before) I will rather give a historical overview from my own perspective. It occurs to me that one way to start this little review is to describe some of the highlights of the Nobel Symposium 1983 on “Steroid Hormone Receptors: Structure and Function”, held in Karlskoga (city where Alfred Nobel had lived), Sweden. Lectures and discussions were published in a special volume “Nobel Symposium No. 57”, edited by Hakan Eriksson (my first student) and me [1]. The meeting was inaugurated by the Swedish King and Queen and attended by most of the high-profile researchers in the nuclear receptor field at the time. The subjects discussed reflect quite well the state of the art and the prevailing ideas about where we were going. The mystery of how binding to ligand resulted in the ability of the receptor to bind to DNA was being addressed by biochemical characterization of the structure of steroid receptors. The purification of these proteins from tissues was then (and would be today) an intensely laborious job, which was complicated by the sensitivity of these proteins to proteolytic degradation. It has to be remembered that, at the time, steroid receptors had not yet been cloned so they had to be traced by labeling with tritiated ligands like dexamethasone, estradiol and 5a-dihydrotestosterone. Jean-Pierre Raynaud, then at Roussel-Uclaf in Paris, had led the development of non-metabolizable ligands like R 1881 for the androgen receptor and R 5020 for the progesterone receptor and this considerably facilitated the work with these receptors [2]. Our own group presented data on the structure of the glucocorticoid
* Correspondence address: University of Houston, Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, 3605 Cullen Blvd, SERC Bldg 545, 3rd Floor, Houston, TX 77204, United States. Tel.: +1 8328424749.
receptor (GR) with which we had been working since the early 1970’s. With limited proteolytic digestion we found that the receptor was composed of three distinct domains: the ligand-binding domain, the DNA-binding domain and the immunoreactive domain [3]. The full-length GR had a molecular weight of 94 K; the combined DNA- and ligand-binding domains 39 K and the ligand-binding domain 19 K. The immunoreactive domain (later shown to be the N-terminal domain) was discovered using mono- and polyclonal anti-GR antibodies developed in our laboratory following our purification of the GR to homogeneity [4]. Interestingly, we found the N-terminal domain to be more sensitive to proteolytic digestion than the other two domains. Later on, the reason for the sensitivity of the N-terminal domain became clear: it is very unstructured and accessible to proteases. The three-domain structure of GR was subsequently shown to be characteristic for all nuclear receptors. Other contributions to the session on steroid receptor structure were from the laboratories of Bert O'Malley and Etienne-Emile Baulieu. The O'Malley laboratory described two forms of the chick oviduct progesterone receptor (PR), A and B; the smaller A receptor bound more strongly to DNA than the B form. Later research has established that both the B form and the A form are encoded by the same gene with the B form being the longer protein. Baulieu reported on a “non-transformed”, “non-activated”, “8S” form of PR that was converted to a “4S” form under high salt condition. The “8S” form contained both liganded PR and a 90 K non-progesterone-binding protein, later shown to be a heat shock protein (hsp90). A few years later the nature of the 8S and 4S forms of various hormone receptors was clarified; hsp90 was shown by other labs, including ours, to bind to the GR ligand-binding domain as a dimer. The binding stabilized the receptor in a ligand-accepting conformation. Upon binding to ligand, the hsp90 dissociated from the receptor, enabling it to bind to DNA [5]. Specific DNA-binding of steroid receptors was the theme of yet another session of the 1983 Nobel Symposium. This aspect of
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steroid receptor biology is, of course, extremely important. During the 1970’s many groups had found that steroid receptors interacted nonspecifically with DNA but this did not explain how the receptors could turn on the transcription of specific genes. Farhang Payvar from Keith Yamamoto's group and Orjan Wrange from our group used DNA purified from the mammary tumor virus (MTV) and showed that there were specific sites on DNA with which purified GR interacted [6,7]. Five specific binding sites, two of which located in the MTV LTR regions, were found. The site in the 50 LTR was shown to confer glucocorticoid responsiveness to downstream genes and was called glucocorticoid response element (GRE) [8]. These findings marked the entrance of steroid receptor research into a more molecular era. The demonstration of specific binding of GR to GRE was made possible by the combined efforts of two research groups, ours with highly purified, homogeneous receptor, and Yamamoto’s with an isolated, GR-sensitive gene, MTV. Subsequent research showed that GR binds to GRE as a homodimer. There was also a session in the symposium on the physiology of steroid receptors. This session was introduced by Elwood Jensen, celebrated for his discovery at the end of the 1950’s of the estrogen receptor (ER) alpha, which Jensen called “estrophilin”. In his Nobel Symposium lecture 1983, he described his development of monoclonal antibodies against the receptor and the use of these reagents to measure ERalpha in human breast cancer as a means to predict hormone responsiveness. On a similar theme, Marc Lippman described ERalpha in MCF-7 breast cancer cells and how its ligand estradiol-17beta stimulated proliferation of these cells. MCF-7 cells later became a generally used model system to study tumorigenic properties of ERalpha. Other well-known researchers who gave lectures during the 1983 Symposium were Brad Thompson (GR in steroid-sensitive and – resistant leukemic cells), Edwin Milgrom (progesterone receptor), Donald Coffey (nuclear matrix), Robert Schimke (mechanism of drug resistance), Arun Roy (alpha2-urinary globulin), Shutsung Liao (androgen receptor), Olli Janne (androgen receptor) and Anthony Norman (vitamin D receptor). Overall, the 1983 Nobel Symposium shows how advanced the nuclear receptor field was already “BC” (before cloning). The basic, three-domain structure (steroid binding-, DNA-binding and “immunoreactive” (later called the N-terminal domain) domains) had been discovered. Specific binding of GR to GREs had been found. After GREs had been reported, a series of confirmatory studies with other nuclear receptors followed, showing that indeed all steroid hormone responsive elements were steroid-activated enhancers of gene transcription. With the access to poly- and mono-clonal antibodies to steroid receptors it became possible to clone these proteins. Since the mRNAs of nuclear receptors are expressed at extremely low levels in tissues, it took some time with the available techniques to carry out this task. The first breakthrough resulted from the continued collaboration between the groups of Yamamoto and myself and was published in 1984 [9]. In a Nature paper we described the cloning of a part of the GR cDNA and used this to perform Northern blots of GR mRNA from several lymphoma cell lines with aberrant glucocorticoid signaling. This was the first published study of nuclear receptor mRNAs. One year later, Evans’ group published the full length GR cDNA in the same journal and confirmed the three-domain structure of nuclear receptors [10]. Our own full length GR cDNA publication followed a few months later in Cell [11]. The DNA-binding domain turned out to consist of two zinc fingers. Because the two zinc finger domain was conserved in all nuclear receptors, the race was on to clone all members of this family by cross hybridization based on the nucleotide sequence of GR cDNA. Several groups described new proteins with the typical
three-domain structure, showing that the nuclear receptor family contained more members than just the steroid hormone receptors. Some of these new proteins had a bona fide ligand binding domain but without a well defined ligand, at least initially. They were called “orphan receptors” and are the main subject of the present volume. The first examples were the estrogen related receptors (alpha, beta and gamma) reported by the Evans group [12]. Whether or not there are physiological ligands for these proteins is still the subject of discussion. In addition to the orphan receptors other new members of the nuclear receptor family were also cloned. Some of these were receptors that were already well known, such as the thyroid hormone receptor (TR alpha and beta; Vennstrom and Evans) [13,14] and the all-trans retinoic acid receptor (RAR alpha, beta and gamma; Chambon and Evans) [15,16]. A relative to RAR, H-2RIIBP, was cloned soon afterwards by Hamada et al. [17]; it was later renamed retinoid X receptor (RXR) beta [18] and Zhang et al. [19] and Marks et al. [20] showed the importance of this receptor in nuclear receptor signaling as it is the heterodimeric partner of orphan and other nuclear receptors. The true nature of the physiological ligand of RXR is still a matter of some debate but this function has been ascribed to 9-cis retinoic acid [21,22]. A prerequisite for a full understanding of the mechanism of action of nuclear receptors is knowledge of their 3-D structure. It has proven to be quite difficult to reach this goal. Until the cloning of nuclear receptor genes, high-resolution structural studies could not have happened because of the difficulties of purifying to homogeneity receptor quantities necessary for such studies. The development of good expression systems for expression of the cloned cDNAs provided structural biochemists with high quality purified receptors in large quantities. The first domain structure to be solved was the DNA-binding domain (DBD) of GR. This was achieved with NMR and was carried out in a collaboration between the laboratories of Härd et al. [23]. Important parts of the structure were two a-helices, one of which entered the major groove of DNA with the second a-helix perpendicular to the first. Later studies of the 3-D structures of other nuclear receptor DBD:s showed that all of them shared the same overall structure as the GR DBD. The ligand-binding domain (LBD) 3-D structure was first solved for the TR (Wagner et al.) [24] and RAR (Renaud et al.) [25]. When compared to a previously published structure of non-liganded RXR [26], it was suggested that when the ligand binds to the LBD, helix 12 folds over the ligand, constituting a roof over the ligand-binding cavity (“mouse trap model”). This concept still needs to be confirmed by further studies. In a later investigation, Hubbard, Carlquist and Gustafsson compared the 3-D structures of ERa bound to an agonist (estradiol-17b) or an antagonist (raloxifene) and concluded that the antagonist, through its long side arm, displaces helix 12 so that it precludes the binding of a co-activator [27]. This mechanism of action of ER antagonists was later confirmed by others. High-resolution quaternary multi-domain structures of nuclear receptors have been extremely difficult to obtain. At least part of the problem is attributable to the non-structured nature of the Nterminal domain (NTD) making it very sensitive to proteolytic degradation and difficult to crystallize. Over the recent several years only three such structures have been obtained, PPARa/RXRa heterodimer and HNF4 homodimer (Chandra et al.) [28,29] and LXRb/RXRa heterodimer (Lou et al.) [30]. In all three cases the crystal structures contained the LBD, DBD, part of the NTD, ligand (except for HNF4), coactivator peptide and DNA (DR1 for PPARa/ RXRa and HNF4, DR4 for LXRb/RXRa). In case of the DR1 bound complexes the domains appear quite tightly packed whereas the DR4 bound heterodimer shows a high degree of flexibility between the domains. These differences will help in the understanding of why different heterodimers bind to DR1, 2, 3 and 4, respectively.
Please cite this article in press as: J.-A. Gustafsson, Historical overview of nuclear receptors, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi. org/10.1016/j.jsbmb.2015.03.004
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Several reviews have been written about nuclear receptor co-activators and co-repressors. Therefore, although very important, these aspects of nuclear receptor mechanisms of action will not be treated further here. However, this review will touch upon the theme of physiological and pathophysiological aspects of nuclear receptors. Over the recent two decades much attention has been paid to the involvement of nuclear receptors in reproduction, metabolism (obesity, diabetes), cancer and CNS function, including stress [31]. One of the initial events in this development was the demonstration that one of the orphan receptors, PPARa, was activated by a whole range of fatty acids at micromolar concentrations [32]. This crucial result contrasted to previous findings that steroid hormones activate nuclear receptors at nanomolar levels. Furthermore, it demonstrated that important molecules in nutrition and metabolism could control the activity of nuclear receptors. Soon these findings were confirmed in several laboratories and it became apparent that the PPAR isoforms could bind a wide array of fatty acids and fatty acid metabolites. The previous concept of the narrow and high ligand specificity of nuclear receptors, like the steroid hormone receptors, thus had to be modified. Another nuclear receptor binding lipids and regulating lipid metabolism is Liver X Receptor (LXRalpha and LXRbeta), a misnomer since only LXRalpha is present in significant quantities in the liver. LXRbeta is ubiquitously expressed including in some non-hepatocyte liver cell types such as those that comprise the biliary tree [33]. The nature of the physiological ligand(s) of LXR is still not firmly established although oxygenated cholesterol metabolites appear to be good candidates [34]. However, other molecules of widely differing nature such as glucose and bile acids have also been claimed to be endogenous activators of LXR. The promiscuous nature of LXR ligands is reminiscent of that of the PPAR isoforms. It is tempting to speculate that these transcriptional regulators of lipid metabolism may be activated by tissue- and context-dependent ligands. A new area of great importance where LXRbeta seems very essential is the CNS. In adult mice this receptor is only expressed in microglia where it plays a role in the proper functioning of neurons in the substantia nigra. Deletion of LXRbeta results in Parkinsonism/ALS syndrome [35]. Furthermore, this receptor is essential for differentiation of radial glial cells to oligodendrocytes and thus for myelination of axons [36]. During development, LXRbeta is expressed in neuronal stem cells in the ventral midbrain and participates in the differentiation of these cells to dopamine containing neurons [37]. These findings indicate that LXRbeta might be a therapeutic target in multiple sclerosis and Parkinson’s disease. The discovery of a second estrogen receptor, ERbeta, was one of the most surprising events in the cloning of nuclear receptors [38]. Before this it had generally been assumed that “Jensen’s ER”, now renamed ERalpha, was the only ER. The multiple and sometimes opposing effects of estradiol all had to be explained in the context of a single receptor and all tissues which responded to estradiol but did not express this ER (lung and prostate included) were deemed to be indirect targets of estradiol. The ERbeta gene is localized on human chromosome 14, ERalpha on chromosome 6. In general terms, the two ERs often have a yin/yang relationship. For instance, ERalpha is pro-proliferative in the mammary gland whereas ERbeta is anti-proliferative. This particular characteristic of ERbeta makes it a possible therapeutic target in several cancers, e.g. breast, colon and prostate. The LBD:s of ERalpha and ERbeta, respectively, are different enough that it was possible for chemists to synthesize ERbeta specific agonists. Such compounds are now in clinical trials, not only against proliferative diseases but also against certain CNS ailments as schizophrenia since ERbeta is also expressed in several areas of the brain implicated in CNS diseases [39].
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In summary, the field of nuclear receptors has undergone an astounding evolution since Elwood Jensen’s discovery of ERalpha at the end of the 50’s. Nevertheless, important gaps in our knowledge remain to be addressed. High resolution quaternary structures of full length nuclear receptors interacting with full length co-activator and co-repressor proteins, if possible also with other components of the transcriptional machinery, are necessary for a more complete understanding of nuclear receptor action. The nature of the physiological ligands of nuclear receptors needs to be revisited and the traditional activators of these proteins must be complemented with novel alternatives. New knowledge of ligands of nuclear receptors will lead to better understanding of the role of these regulatory molecules in physiology and disease and therefore create novel therapeutic drug opportunities. A particularly exciting, evolving field is the gut microbiome, which has been called “a new endocrine organ” [40], continuously secreting bacterial metabolites and components with remarkable effects on the host’s homeostasis. Many orphan receptors still need to be de-orphanized and in this context, perturbation of the physiological effects of receptor-interacting endocrine disruptors, particularly in the fetal and neonatal periods, requires urgent attention. It should not be overlooked that many of these novel receptors are expressed in the central nervous system and they provide us with a new understanding of, and possibly novel targets for, the bane of our society, namely neurodegenerative disorders.
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This work has been supported by the Robert A. Welch Q7 Foundation (E-0004).
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