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1.  Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells 
The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases.
PMCID: PMC3960937  PMID: 24653668
2.  Post-translational modifications of nuclear receptors and human disease 
Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARγ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy’s Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.
PMCID: PMC3309075  PMID: 22438791
3.  Use of differential scanning fluorimetry as a high-throughput assay to identify nuclear receptor ligands  
Identification of ligands that interact with nuclear receptors is both a major biological problem and an important initial step in drug discovery. Several in vitro and in vivo techniques are commonly used to screen ligand candidates against nuclear receptors; however, none of the current assays allow screening without modification of either the protein and/or the ligand in a high-throughput fashion. Differential scanning fluorimetry (DSF) allows unmodified potential ligands to be screened as 10µL reactions in 96-well format against partially purified protein, revealing specific interactors. As a proof of principle, we used a commercially-available nuclear receptor ligand candidate chemical library to identify interactors of the human estrogen receptor α ligand binding domain (ERα LBD). Compounds that interact specifically with ERα LBD stabilize the protein and result in an elevation of the thermal denaturation point, as monitored by the environmentally-sensitive dye SYPRO orange. We successfully identified all three compounds in the library that have previously been identified to interact with ERα, with no false positive results.
PMCID: PMC3309076  PMID: 22438792
4.  EMBO Retinoids 2011: mechanisms, biology and pathology of signaling by retinoic acid and retinoic acid receptors 
Retinoic acid (RA) is one of the principal active metabolites of vitamin A (retinol) which mediates a spectrum of critical physiological and developmental processes. Transcriptional regulation by RA is mediated primarily by members of the retinoic acid receptor (RAR) subfamily of the nuclear receptor (NR) superfamily of transcription factors. NRs bind specific genomic DNA sequence motifs and engage coregulators and components of the basal transcription machinery to effect transcriptional regulation at target gene promoters. Disruption of signaling by retinoic acid is thought to underlie the etiology of a number of inflammatory and neoplastic diseases including breast cancer and haematological malignancies. A meeting of international researchers in retinoid signaling was convened in Strasbourg in September 2011 under the auspices of the European Molecular Biology Organization (EMBO). Retinoids 2011 encompassed myriad mechanistic, biological and pathological aspects of these hormones and their cognate receptors, as well as setting these advances in the context of wider current questions on signaling by members of the NR superfamily.
PMCID: PMC3309077  PMID: 22438793
5.  Mutual information identifies sequence positions conserved within the nuclear receptor superfamily: approach reveals functionally important regions for DNA binding specificity  
Members of the nuclear receptor superfamily differentiate in terms of specificity for DNA recognition and binding, oligomeric state, and ligand binding. The wide range of specificities are impressive given the high degree of sequence conservation in the DNA binding domain (DBD) and moderate sequence conservation with high structural similarity within the ligand binding domains (LBDs). Determining sequence positions that are conserved within nuclear receptor subfamilies can provide important indicators into the structural dynamics that translate to oligomeric state of the active receptor, DNA binding specificity and ligand affinity and selectivity. Here we present a method to analyze sequence data from all nuclear receptors that facilitates detection of co-evolving pairs using Mutual Information (MI). Using this method we demonstrate that MI can reveal functionally important sequence positions within the superfamily and the approach identified three sequence positions that have conserved sequence patterns across all nuclear receptors and subfamilies. Interestingly, two of the sequence positions identified are located within the DBD CII and the third was within Helix c of the DBD. These sequences are located within the heterodimer interface of PPARγ (CII) and RXRα (Helix c) based on PDB:3DZU. Helix c of PPARγ, which is not involved in the DBD dimer interface, binds the minor groove in the 5' flanking region in a consensus PPARγ response element (PPRE) and the corresponding RXRα (CII) is found in the 3' flanking region of RXRE (3DZU). As these three sequence positions represent unique identifiers for all nuclear receptors and they are located within the dimer interface of PPARγ-RXRα DBD (3DZU) interfacing with the flanking regions of the NRRE, we conclude they are critical sequence positions perhaps dictating nuclear receptor (NR) DNA binding specificity.
PMCID: PMC3049237  PMID: 21383938
6.  Deciphering the nuclear bile acid receptor FXR paradigm 
Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use.
PMCID: PMC3049226  PMID: 21383957
7.  Nuclear receptor Rev-erbα: a heme receptor that coordinates circadian rhythm and metabolism  
Nuclear receptor Rev-erbα (NR1D1), previously considered to be an orphan nuclear receptor, is a receptor for heme, which promotes transcriptional repression via recruitment of the NCoR-HDAC3 corepressor complex. Rev-erbα gene regulation is circadian, and Rev-erbα comprises a critical negative limb of the core circadian clock by directly repressing the expression of the positive clock component, Bmal1. Rev-erbα also regulates the metabolic gene pathway, thus serving as a heme sensor for coordination of circadian and metabolic pathways.
PMCID: PMC2858265  PMID: 20414452
8.  PPARα: energy combustion, hypolipidemia, inflammation and cancer  
The peroxisome proliferator-activated receptor α (PPARα, or NR1C1) is a nuclear hormone receptor activated by a structurally diverse array of synthetic chemicals known as peroxisome proliferators. Endogenous activation of PPARα in liver has also been observed in certain gene knockout mouse models of lipid metabolism, implying the existence of enzymes that either generate (synthesize) or degrade endogenous PPARα agonists. For example, substrates involved in fatty acid oxidation can function as PPARα ligands. PPARα serves as a xenobiotic and lipid sensor to regulate energy combustion, hepatic steatosis, lipoprotein synthesis, inflammation and liver cancer. Mainly, PPARα modulates the activities of all three fatty acid oxidation systems, namely mitochondrial and peroxisomal β-oxidation and microsomal ω-oxidation, and thus plays a key role in energy expenditure. Sustained activation of PPARα by either exogenous or endogenous agonists leads to the development of hepatocellular carcinoma resulting from sustained oxidative and possibly endoplasmic reticulum stress and liver cell proliferation. PPARα requires transcription coactivator PPAR-binding protein (PBP)/mediator subunit 1(MED1) for its transcriptional activity.
PMCID: PMC2858266  PMID: 20414453
9.  DamIP: A novel method to identify DNA binding sites in vivo  
Identifying binding sites and target genes of transcription factors is a major biologic problem. The most commonly used current technique, chromatin immunoprecipitation (ChIP), is dependent on a high quality antibody for each protein of interest, which is not always available, and is also cumbersome, involving sequential cross-linking and reversal of cross-linking. We have developed a novel strategy to study protein DNA binding sites in vivo, which we term DamIP. By tethering a mutant form of E. coli DNA adenine methyltransferase to the target protein, the fusion protein introduces N-6-adenosine methylation to sequences proximal to the protein binding sites. DNA fragments with this modification, which is absent in eukaryotes, are detected using an antibody directed against methylated adenosine. For an initial test of the method we used human estrogen receptor α (hERα), one of the best studied transcription factors. We found that expression of Dam-hERα fusion proteins in MCF-7 cells introduces adenosine methylation near a series of known direct hERα binding sites. Specific methylation tags are also found at indirect hERα binding sites, including both primary binding sites for the ER interactors AP-1 and SP1, and promoters that are activated by upstream ER bound enhancers. DamIP provides a new tool for the study of DNA interacting protein function in vivo.
PMCID: PMC2858267  PMID: 20419059
10.  PPARγ1 and LXRα face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1 
Peroxisome proliferator-activated receptor γ1 (PPARγ1) and liver X receptor α (LXRα) are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation; key biological processes in atherogenesis. The activation of PPARγ1 and LXRα by natural or synthetic ligands results in the transactivation of ABCA1, ABCG1, and ApoE; integral players in cholesterol efflux and reverse cholesterol transport. In this review, we describe the structure, isoforms, expression pattern, and functional specificity of PPARs and LXRs. Control of PPARs and LXRs transcriptional activity by coactivators and corepressors is also highlighted. The specific roles that PPARγ1 and LXRα play in inducing macrophage cholesterol efflux mediators and antagonizing macrophage inflammatory responsiveness are summarized. Finally, this review focuses on the recently reported regulatory functions that adipocyte enhancer-binding protein 1 (AEBP1) exerts on PPARγ1 and LXRα transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation.
PMCID: PMC2858268  PMID: 20419060
11.  Control of oocyte release by progesterone receptor-regulated gene expression  
The progesterone receptor (PGR) is a nuclear receptor transcription factor that is essential for female fertility, in part due to its control of oocyte release from the ovary, or ovulation. In all mammals studied to date, ovarian expression of PGR is restricted primarily to granulosa cells of follicles destined to ovulate. Granulosa cell expression of PGR is induced by the pituitary Luteinizing Hormone (LH) surge via mechanisms that are not entirely understood, but which involve activation of Protein Kinase A and modification of Sp1/Sp3 transcription factors on the PGR promoter. Null mutations for PGR or treatment with PGR antagonists block ovulation in all species analyzed, including humans. The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture. Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR. Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes.
PMCID: PMC2807638  PMID: 20087433
12.  Nuclear hormone receptor architecture - form and dynamics: The 2009 FASEB Summer Conference on Dynamic Structure of the Nuclear Hormone Receptors  
Nuclear hormone receptors (NHRs) represent a large and diverse family of ligand-activated transcription factors involved in regulating development, metabolic homeostasis, salt balance and reproductive health. The ligands for these receptors are typically small hydrophobic molecules such as steroid hormones, thyroid hormone, vitamin D3 and fatty acid derivatives. The first NHR structural information appeared ~20 years ago with the solution and crystal structures of the DNA binding domains and was followed by the structure of the agonist and antagonist bound ligand binding domains of different NHR members. Interestingly, in addition to these defined structural features, it has become clear that NHRs also possess significant structural plasticity. Thus, the dynamic structure of the NHRs was the topic of a recent stimulating and informative FASEB Summer Research Conference held in Vermont.
PMCID: PMC2807637  PMID: 20087432
13.  Hairless is a nuclear receptor corepressor essential for skin function  
The activity of nuclear receptors is modulated by numerous coregulatory factors. Corepressors can either mediate the ability of nuclear receptors to repress transcription, or can inhibit transactivation by nuclear receptors. As we learn more about the mechanisms of transcriptional repression, the importance of repression by nuclear receptors in development and disease has become clear. The protein encoded by the mammalian Hairless (Hr) gene was shown to be a corepressor by virtue of its functional similarity to the well-established corepressors N-CoR and SMRT. Mutation of the Hr gene results in congenital hair loss in both mice and men. Investigation of Hairless function both in vitro and in mouse models in vivo has revealed a critical role in maintaining skin and hair by regulating the differentiation of epithelial stem cells, as well as a putative role in regulating gene expression via chromatin remodeling.
PMCID: PMC2807636  PMID: 20087431
14.  Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression  
Progesterone is a critical regulator of normal female reproductive function, with diverse tissue-specific effects in the human. The effects of progesterone are mediated by its nuclear receptor (PR) that is expressed as two isoforms, PRA and PRB, which are virtually identical except that PRA lacks 164 amino acids that are present at the N-terminus of PRB. Considerable in vitro evidence suggests that the two PRs are functionally distinct and in animals, tissue-specific distribution patterns of PRA and PRB may account for some of the diversity of progesterone effects. In the human, PRA and PRB are equivalently expressed in most target cells, suggesting that alternative mechanisms control the diversity of progesterone actions. PR mediates the effects of progesterone by association with a range of coregulatory proteins and binding to specific target sequences in progesterone-regulated gene promoters. Ligand activation of PR results in redistribution into discrete subnuclear foci that are detectable by immunofluorescence, probably representing aggregates of multiple transcriptionally active PR-coregulator complexes. PR foci are aberrant in cancers, suggesting that the coregulator composition and number of complexes is altered. A large family of coregulators is now described and the range of proteins known to bind PR exceeds the complement required for transcriptional activation, suggesting that in the human, tissue-specific coregulator expression may modulate progesterone response. In this review, we examine the role of nuclear localization of PR, coregulator association and tissue-specific expression in modulating progesterone action in the human.
PMCID: PMC2807635  PMID: 20087430
15.  Erk signaling and chromatin remodeling in MMTV promoter activation by progestins  
Transcription from the mouse mammary tumor virus (MMTV) promoter can be induced by progestins. The progesterone receptor (PR) binds to a cluster of five hormone responsive elements (HREs) and activates the promoter by synergistic interactions with the ubiquitous transcription factor, nuclear factor 1 (NF1). Progesterone treatment of cells in culture leads to activation of the Src/Ras/Erk/Msk1 cascade. Selective inhibition of Erk, or its target kinase Msk1, interferes with chromatin remodeling and blocks MMTV activation. A complex of activated PR, Erk and Msk1 is recruited to promoter after 5 min of hormone treatment and phosphorylates histone H3 at serine 10. This modification promotes the displacement of HP1γ and subsequent chromatin remodeling. Progestin treatment leads to the recruitment of the BAF complex, which selectively displaces histones H2A and H2B from the nucleosome containing the HREs. The acetyltransferase PCAF is also required for induction of progesterone target genes and acetylates histone H3 at K14, an epigenetic mark, which interacts with Brg1 and Brm, anchoring the BAF complex to chromatin. In nucleosomes assembled on either MMTV or mouse rDNA promoter sequences, SWI/SNF displaces histones H2A and H2B from MMTV, but not from the rDNA nucleosome. Thus, the outcome of nucleosome remodeling by purified SWI/SNF depends on DNA sequence. The resultant H3/H4 tetramer particle is then the substrate for subsequent events in induction. Thus, initial activation of the MMTV promoter requires activation of several kinases and PCAF leading to phosphoacetylation of H3, and recruitment of BAF with subsequent removal of H2A/H2B.
PMCID: PMC2807634  PMID: 20087429
16.  Naturally occurring C-terminal splice variants of nuclear receptors  
Alternative mRNA splicing in the region encoding the C-terminus of nuclear receptors results in receptor variants lacking the entire ligand-binding domain (LBD), or a part of it, and instead contain a sequence of splice variant-specific C-terminal amino acids. A total of thirteen such splice variants have been shown to occur in vertebrates, and at least nine occur in humans. None of these receptor variants appear to be able to bind endogenous ligands and to induce transcription on promoters containing the response element for the respective canonical receptor variant. Interestingly, ten of these C-terminal splice variants have been shown to display dominant-negative activity on the transactivational properties of their canonical equivalent. Research on most of these splice variants has been limited, and the dominant-negative effect of these receptor variants has only been demonstrated in reporter assays in vitro, using transiently transfected receptors and reporter constructs. Therefore, the in vivo function and relevance of most C-terminal splice variants remains unclear. By reviewing the literature on the human glucocorticoid receptor β-isoform (hGRβ), we show that the dominant-negative effect of hGRβ is well established using more physiologically relevant readouts. The hGR β-isoform may alter gene transcription independent from the canonical receptor and increased hGRβ levels correlate with glucocorticoid resistance and the occurrence of several immune-related diseases. Thus, available data suggests that C-terminal splice variants of nuclear receptors act as dominant-negative inhibitors of receptor-mediated signaling in vivo, and that aberrant expression of these isoforms may be involved in the pathogenesis of a variety of diseases.
PMCID: PMC2716050  PMID: 19636396
17.  Developmental expression of retinoic acid receptors (RARs) 
Here, I review the developmental expression features of genes encoding the retinoic acid receptors (RARs) and the 'retinoid X' or rexinoid receptors (RXRs). The first detailed expression studies were performed in the mouse over two decades ago, following the cloning of the murine Rar genes. These studies revealed complex expression features at all stages of post-implantation development, one receptor gene (Rara) showing widespread expression, the two others (Rarb and Rarg) with highly regionalized and/or cell type-specific expression in both neural and non-neural tissues. Rxr genes also have either widespread (Rxra, Rxrb), or highly-restricted (Rxrg) expression patterns. Studies performed in zebrafish and Xenopus demonstrated expression of Rar and Rxr genes (both maternal and zygotic), at early pre-gastrulation stages. The eventual characterization of specific enzymes involved in the synthesis of retinoic acid (retinol/retinaldehyde dehydrogenases), or the triggering of its catabolism (CYP26 cytochrome P450s), all of them showing differential expression patterns, led to a clearer understanding of the phenomenons regulated by retinoic acid signaling during development. Functional studies involving targeted gene disruptions in the mouse, and additional approaches such as dominant negative receptor expression in other models, have pinpointed the specific, versus partly redundant, roles of the RARs and RXRs in many developing organ systems. These pleiotropic roles are summarized hereafter in relationship to the receptors’ expression patterns.
PMCID: PMC2686085  PMID: 19471585
18.  Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs) 
Nuclear retinoic acid receptors (RARs) are transcriptional regulators controlling the expression of specific subsets of genes in a ligand-dependent manner. The basic mechanism for switching on transcription of cognate target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes, the assembly of which is directed by the C-terminal ligand-binding domain of RARs. In addition to this scenario, new roles for the N-terminal domain and the ubiquitin-proteasome system recently emerged. Moreover, the functions of RARs are not limited to the regulation of cognate target genes, as they can transrepress other gene pathways. Finally, RARs are also involved in nongenomic biological activities such as the activation of translation and of kinase cascades. Here we will review these mechanisms, focusing on how kinase signaling and the proteasome pathway cooperate to influence the dynamics of RAR transcriptional activity.
PMCID: PMC2686084  PMID: 19471584
19.  A novel approach to investigate the subcellular distribution of nuclear receptors in vivo  
Subcellular compartmentalisation and the intracellular movement of nuclear receptors are major regulatory steps in executing their transcriptional function. Though significant progress has been made in understanding these regulatory processes in cultured mammalian cells, such results have rarely been confirmed within cells of a living mammal. This article describes a simple, time-efficient approach to study the nuclear versus cytoplasmic accumulation of nuclear receptors and the regions of nuclear receptor proteins that govern subcellular trafficking within hepatocytes of live mice. Pregnane X receptor, a xenobiotic-activated member of the nuclear receptor family, was used to exemplify the approach. Using dual-labeled wild-type and mutant PXR expression constructs, we outline their in vivo delivery, simultaneous cellular expression, visualization and categorical classification within hepatocytes of live mice. Using this approach, we identified three mutants that had an altered subcellular distribution in the presence and absence of a PXR ligand. This novel in vivo method complements the current cell culture-based experimental systems in protein subcellular localisation studies.
PMCID: PMC2686083  PMID: 19471583
20.  Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism  
The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORα, -β, and -γ (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORα plays a critical role in the development of the cerebellum, that both RORα and RORβ are required for the maturation of photoreceptors in the retina, and that RORγ is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORγ in lineage specification of uncommitted CD4+ T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors.
PMCID: PMC2670432  PMID: 19381306
21.  Function of retinoic acid receptors during embryonic development  
Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation and homeostasis. Studies performed in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the RAR and RXR nuclear receptors. However, in vitro studies indicate what is possible, but not necessarily what is actually occurring in vivo, because they are performed under non-physiological conditions. Therefore, genetic approaches in the animal have been be used to determine the physiological functions of retinoid receptors. Homologous recombination in embryonic stem cells has been used to generate germline null mutations of the RAR- and RXR-coding genes in the mouse. As reviewed here, the generation of such germline mutations, combined with pharmacological approaches to block the RA signalling pathway, has provided genetic evidence that RAR/RXR heterodimers are indeed the functional units transducing the RA signal during prenatal development. However, due to (i) the complexity in “hormonal” signalling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given family, and (iii) in utero or early postnatal lethality of certain germline null mutations, these genetic studies have failed to reveal all the physiological functions of RARs and RXRs, notably in adults. Spatio-temporally-controlled somatic mutations generated in given cell types/tissues and at chosen times during postnatal life, will be required to reveal all the functions of RAR and RXR throughout the lifetime of the mouse.
PMCID: PMC2670431  PMID: 19381305
22.  The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism  
The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a nuclear hormone receptor activated by a diverse array of endogenous hormones, dietary steroids, pharmaceutical agents, and xenobiotic compounds. SXR has an enlarged, flexible, hydrophobic ligand binding domain (LBD) which is remarkably divergent across mammalian species and SXR exhibits considerable differences in its pharmacology among mammals. The broad response profile of SXR has led to the development of "the steroid and xenobiotic sensor hypothesis". SXR has been established as a xenobiotic sensor that coordinately regulates xenobiotic clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism. In the past few years, research has revealed new and mostly unsuspected roles for SXR in modulating inflammation, bone homeostasis, vitamin D metabolism, lipid homeostasis, energy homeostasis and cancer. The identification of SXR as a xenobiotic sensor has provided an important tool for studying new mechanisms through which diet, chemical exposure, and environment ultimately impact health and disease. The discovery and pharmacological development of new PXR modulators might represent an interesting and innovative therapeutic approach to combat various diseases.
PMCID: PMC2646121  PMID: 19240808
23.  Selective androgen receptor modulators in preclinical and clinical development  
Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.
PMCID: PMC2602589  PMID: 19079612
24.  Atrophin proteins: an overview of a new class of nuclear receptor corepressors  
The normal development and physiological functions of multicellular organisms are regulated by complex gene transcriptional networks that include myriad transcription factors, their associating coregulators, and multiple chromatin-modifying factors. Aberrant gene transcriptional regulation resulting from mutations among these elements often leads to developmental defects and diseases. This review article concentrates on the Atrophin family proteins, including vertebrate Atrophin-1 (ATN1), vertebrate arginine-glutamic acid dipeptide repeats protein (RERE), and Drosophila Atrophin (Atro), which we recently identified as nuclear receptor corepressors. Disruption of Atrophin-mediated pathways causes multiple developmental defects in mouse, zebrafish, and Drosophila, while an aberrant form of ATN1 and altered expression levels of RERE are associated with neurodegenerative disease and cancer in humans, respectively. We here provide an overview of current knowledge about these Atrophin proteins. We hope that this information on Atrophin proteins may help stimulate fresh ideas about how this newly identified class of nuclear receptor corepressors aids specific nuclear receptors and other transcriptional factors in regulating gene transcription, manifesting physiological effects, and causing diseases.
PMCID: PMC2586093  PMID: 19043594
25.  Diverse roles of androgen receptor (AR) domains in AR-mediated signaling  
Androgens control male sexual development and maintenance of the adult male phenotype. They have very divergent effects on their target organs like the reproductive organs, muscle, bone, brain and skin. This is explained in part by the fact that different cell types respond differently to androgen stimulus, even when all these responses are mediated by the same intracellular androgen receptor. To understand these tissue- and cell-specific readouts of androgens, we have to learn the many different steps in the transcription activation mechanisms of the androgen receptor (NR3C4). Like all nuclear receptors, the steroid receptors have a central DNA-binding domain connected to a ligand-binding domain by a hinge region. In addition, all steroid receptors have a relatively large amino-terminal domain. Despite the overall structural homology with other nuclear receptors, the androgen receptor has several specific characteristics which will be discussed here. This receptor can bind two types of androgen response elements (AREs): one type being similar to the classical GRE/PRE-type elements, the other type being the more divergent and more selective AREs. The hormone-binding domain has low intrinsic transactivation properties, a feature that correlates with the low affinity of this domain for the canonical LxxLL-bearing coactivators. For the androgen receptor, transcriptional activation involves the alternative recruitment of coactivators to different regions in the amino-terminal domain, as well as the hinge region. Finally, a very strong ligand-induced interaction between the amino-terminal domain and the ligand-binding domain of the androgen receptor seems to be involved in many aspects of its function as a transcription factor. This review describes the current knowledge on the structure-function relationships within the domains of the androgen receptor and tries to integrate the involvement of different domains, subdomains and motifs in the functioning of this receptor as a transcription factor with tissue- and cell-specific readouts.
PMCID: PMC2443950  PMID: 18612376

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