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Notable papers are listed here. Papers with two red dots are highly recommended. Articles with one or zero dots are recommended but not essential.
  1. (1992) Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell, 68(2):377-95.
    We have purified and cloned a HeLa cell nuclear protein that strongly stimulates binding of retinoic acid and thyroid hormone receptors (RARs and TRs) to response elements. The purified protein is a human retinoid X receptor beta (hRXR beta). Three murine members of the RXR family (mRXR alpha, beta, and gamma) have also been cloned, and their interactions with RARs and TRs have been investigated. Under conditions where RAR, RXR, and TR bound poorly as homodimers to various response elements, strongly cooperative RAR-RXR and TR-RXR binding was observed. The binding efficiency was dependent on the sequence, relative orientation, and spacing of the repeated motifs of response elements. We show also that unstable RAR-RXR heterodimers were formed in solution, and that C-terminal sequences and the DNA-binding domains of both receptors were required for efficient formation of stable heterodimers on response elements. These findings suggest a convergence of the signaling pathways of some members of the nuclear receptor superfamily.
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  2. Petkovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature, 330(6147):444-50.
    A cDNA encoding a protein that binds retinoic acid with high affinity has been cloned. The protein is homologous to the receptors for steroid hormones, thyroid hormones and vitamin D3, and appears to be a retinoic acid-inducible trans-acting enhancer factor, suggesting that the molecular mechanisms of the effect of retinoids (vitamin A) on embryonic development, differentiation and tumour cell growth are similar to those described for other members of this nuclear receptor family.
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  3. Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature, 330(6149):624-9.
    Analysis of complementary DNA encoding a novel gene product reveals striking similarity to the steroid and thyroid hormone receptors. Binding and transcription activational studies show it to be a receptor for the vitamin A-related morphogen retinoic acid.
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  4. (2010) Ross-Innes CS, Stark R, Holmes KA, Schmidt D, Spyrou C, Russell R, Massie CE, Vowler SL, Eldridge M, Carroll JS. Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer. Genes Dev., 24(2):171-82.
    Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells.
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  5. (2010) Martens JH, Brinkman AB, Simmer F, Francoijs KJ, Nebbioso A, Ferrara F, Altucci L, Stunnenberg HG. PML-RARalpha/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia. Cancer Cell, 17(2):173-85.
    Many different molecular mechanisms have been associated with PML-RARalpha-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARalpha binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARalpha with RXR to the vast majority of these binding regions. Genome-wide epigenetic studies revealed that treatment with pharmacological doses of all-trans retinoic acid induces changes in H3 acetylation, but not H3K27me3, H3K9me3, or DNA methylation at the PML-RARalpha/RXR binding sites or at nearby target genes. Our results suggest that PML-RARalpha/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for hematopoietic differentiation, RAR signaling, and epigenetic control is crucial to its transforming potential.
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  6. (2009) Hua S, Kittler R, White KP. Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell, 137(7):1259-71.
    Retinoic acid (RA) triggers antiproliferative effects in tumor cells, and therefore RA and its synthetic analogs have great potential as anticarcinogenic agents. Retinoic acid receptors (RARs) mediate RA effects by directly regulating gene expression. To define the genetic network regulated by RARs in breast cancer, we identified RAR genomic targets using chromatin immunoprecipitation and expression analysis. We found that RAR binding throughout the genome is highly coincident with estrogen receptor alpha (ERalpha) binding, resulting in a widespread crosstalk of RA and estrogen signaling to antagonistically regulate breast cancer-associated genes. ERalpha- and RAR-binding sites appear to be coevolved on a large scale throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements. The highly coordinated intersection between these two critical nuclear hormone receptor signaling pathways provides a global mechanism for balancing gene expression output via local regulatory interactions dispersed throughout the genome.
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  7. (2005) Balmer JE, Blomhoff R. A robust characterization of retinoic acid response elements based on a comparison of sites in three species. J. Steroid Biochem. Mol. Biol., 96(5):347-54.
    The availability of high-throughput genomic sequencing has allowed us to construct a more robust characterization of retinoic acid response elements than was possible in the past. We located human, mouse, and rat homologs for each of 51 well-documented, conserved retinoic acid response elements. Mathematical and statistical analyses of these 153 sites, 78 of which are new, shows that 92% of response elements have direct-repeat symmetry, but that only 76% exhibit canonical spacing attributes. While the familiar '(a/g)g(g/t)tca' hexamer motif is upheld, the more relaxed sequence, '(a/g)g(g/t)(g/t)(g/c)a', represents a 10% consensus. Sites are as likely to be on the coding strand as on the non-coding strand, and 86% of them are in upstream locations. From a statistical point of view, DR1 elements are fundamentally different from DR2 and DR5 elements, but this is only evident in the 5' hexamer. While there is considerable variation in core positions, and while no nucleotide can be considered forbidden at any position, variation among species at a fixed locus appears surprisingly constrained once a functional site has been attained.
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  8.  review article 
    (2002) Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J. Lipid Res., 43(11):1773-808.
    Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall. We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0).
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  9.  review article 
    (2001) Zelent A, Guidez F, Melnick A, Waxman S, Licht JD. Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene, 20(49):7186-203.
    Acute promyelocytic leukemia (APL) has been recognized as a distinct clinical entity for over 40 years. Although relatively rare among hematopoietic malignancies (approximately 10% of AML cases), this disease has attracted a particularly good share of attention by becoming the first human cancer in which all-trans-retinoic acid (ATRA), a physiologically active derivative of vitamin A, was able to induce complete remission (CR). ATRA induced remission is not associated with rapid cell death, as in the case of conventional chemotherapy, but with a restoration of the 'normal' granulocytic differentiation pathway. With this remarkable medical success story APL has overnight become a paradigm for the differentiation therapy of cancer. A few years later, excitement with APL was further enhanced by the discovery that a cytogenetic marker for this disease, the t(15:17) reciprocal chromosomal translocation, involves a fusion between the retinoic acid receptor alpha (RARalpha) gene and a previously unknown locus named promyelocytic leukemia (PML). Consequence of this gene rearrangement is expression of the PML-RARalpha chimeric oncoprotein, which is responsible for the cellular transformation as well as ATRA response that is observed in APL. Since this initial discovery, a number of different translocation partner genes of RARalpha have been reported in rarer cases of APL, strongly suggesting that disruption of RARalpha underlies its pathogenesis. This article reviews various rearrangements of the RARalpha gene that have so far been described in literature, functions of the proteins encoded by the different RARalpha partner loci, and implications that these may have for the molecular pathogenesis of APL.
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  10. (2000) Rastinejad F, Wagner T, Zhao Q, Khorasanizadeh S. Structure of the RXR-RAR DNA-binding complex on the retinoic acid response element DR1. EMBO J., 19(5):1045-54.
    The 9-cis retinoic acid receptor (retinoid X receptor, RXR) forms heterodimers with the all-trans retinoic acid receptor (RAR) and other nuclear receptors on DNA regulatory sites composed of tandem binding elements. We describe the 1.70 A resolution structure of the ternary complex of RXR and RAR DNA-binding regions in complex with the retinoic acid response element DR1. The receptors recognize identical half-sites through extensive base-specific contacts; however, RXR binds exclusively to the 3' site to form an asymmetric complex with the reverse polarity of other RXR heterodimers. The subunits associate in a strictly DNA-dependent manner using the T-box of RXR and the Zn-II region of RAR, both of which are reshaped in forming the complex. The protein-DNA contacts, the dimerization interface and the DNA curvature in the RXR-RAR complex are distinct from those of the RXR homodimer, which also binds DR1. Together, these structures illustrate how the nuclear receptor superfamily exploits conformational flexibility and locally induced structures to generate combinatorial transcription factors.
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  11. (1993) Mader S, Chen JY, Chen Z, White J, Chambon P, Gronemeyer H. The patterns of binding of RAR, RXR and TR homo- and heterodimers to direct repeats are dictated by the binding specificites of the DNA binding domains. EMBO J., 12(13):5029-41.
    We show here that, in addition to generating an increase in DNA binding efficiency, heterodimerization of retinoid X receptor (RXR) with either retinoic acid receptor (RAR) or thyroid hormone receptor (TR) alters the binding site repertoires of RAR, RXR and TR homodimers. The binding site specificities of both homo- and heterodimers appear to be largely determined by their DNA binding domains (DBDs), and are dictated by (i) homocooperative DNA binding of the RXR DBD, (ii) heterocooperative DNA binding of RXR/RAR and RXR/TR DBDs, and (iii) steric hindrance. No homodimerization domain exists in the DBDs of TR and RAR. The dimerization function which is located in the ligand binding domain further stabilizes, but in general does not change, the repertoire dictated by the corresponding DBD(s). The binding repertoire can be further modified by the actual sequence of the binding site. We also provide evidence supporting the view that the cooperative binding of the RXR/RAR and RXR/TR DBDs to directly repeated elements is anisotropic, with interactions between the dimerization interfaces occurring only with RXR bound to the 5' located motif. This polarity, which appears to be maintained in the full-length receptor heterodimers, may constitute a novel parameter in promoter-specific transactivation.
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  12. (1991) Leroy P, Nakshatri H, Chambon P. Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element. Proc. Natl. Acad. Sci. U.S.A., 88(22):10138-42.
    We have characterized the promoter of the mouse retinoic acid receptor alpha 2 (mRAR-alpha 2) isoform. This promoter contains a retinoic acid response element (RARE) that closely resembles the RARE that is present in the RAR-beta 2 promoter. Moreover, RAR-alpha 2 and RAR-beta 2 proximal promoter sequences are similar to each other and generate transcripts whose respective start sites are located at similar positions. The RAR-alpha 2 RARE consists of two directly repeated 5'-GTTCA-3' motifs to which all three RARs (alpha, beta, and gamma) bind in vitro.
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  13.  review article 
    (2009) Rochette-Egly C, Germain P. Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs). , 7:e005.
    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.
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  14. (2008) Kruse SW, Suino-Powell K, Zhou XE, Kretschman JE, Reynolds R, Vonrhein C, Xu Y, Wang L, Tsai SY, Tsai MJ, Xu HE. Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS Biol., 6(9):e227.
    The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 A crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix alpha10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation.
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  15. (2008) Arriola E, Marchio C, Tan DS, Drury SC, Lambros MB, Natrajan R, Rodriguez-Pinilla SM, Mackay A, Tamber N, Fenwick K, Jones C, Dowsett M, Ashworth A, Reis-Filho JS. Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines. Lab. Invest., 88(5):491-503.
    HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.
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  16. (2008) Huq MD, Ha SG, Wei LN. Modulation of retinoic acid receptor alpha activity by lysine methylation in the DNA binding domain. J. Proteome Res., 7(10):4538-45.
    Metabolic labeling and detection with a methylated lysine-specific antibody confirm lysine methylation of RAR alpha in mammalian cells. We previously reported Lys (347) trimethylation of mouse retinoic acid receptor alpha (RAR alpha) in the ligand binding domain (LBD) that affected ligand sensitivity of the dissected LBD. Here we report two monomethylated residues, Lys (109) and Lys (171) identified by LC-ESI-MS/MS in the DNA binding domain (DBD) and the hinge region, which affect retinoic acid (RA) sensitivity, coregulator interaction and heterodimerization with retinoid X receptor (RXR) in the context of the full-length protein. Constitutive negative mutation at Lys (109), but not Lys (171), reduces RA-dependent activation. Methylation at Lys (109) plays a more dominant role than trimethylation at Lys (347) in terms of RA activation of the full-length receptor. Lys (109) is located in a homologous sequence (CEGC K GFFRRS) of the DBD in RARs and is conserved in the nuclear receptor superfamily even across the species boundary. This study uncovers a potential role for monomethylation at Lys (109) in coordinating the synergy between DBD and LBD for ligand-dependent activation of RAR alpha.
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  17. (2007) Huq MD, Tsai NP, Khan SA, Wei LN. Lysine trimethylation of retinoic acid receptor-alpha: a novel means to regulate receptor function. Mol. Cell Proteomics, 6(4):677-88.
    Retinoic acid receptors (RARs) belong to the nuclear receptor superfamily. The mechanism of ligand-dependent activation of RARs is well known. The effect of protein phosphorylation on the activity of RARs has also been demonstrated. However, it is unclear whether other types of modifications exist and if so whether they can affect the activity of RARs. In a mass spectrometric analysis of mouse RARalpha expressed in insect cells, we identified a trimethylation site on Lys(347) in the ligand binding domain. The modification site was verified in mammalian cells, and site-directed mutagenesis studies revealed the functionality of Lys(347) methylation in vivo. Constitutive negative mutants, mimicking hypomethylated RARalpha, were prepared by replacing methylated Lys(347) with either alanine or glutamine. A constitutive positive mutant partially mimicking the hypermethylated RARalpha was generated by replacing the methylated lysine residue with phenylalanine, a bulky hydrophobic amino acid, to introduce a site-specific hydrophobicity similar to that contributed by lysine methylation. Studies of these mutants revealed that trimethylation of Lys(347) of RARalpha facilitated its interactions with cofactors p300/CREB-binding protein-associated factor and receptor-interacting protein 140 as well as its heterodimeric partner retinoid X receptor, suggesting that site-specific hydrophobicity at Lys(347) enhanced molecular interaction of RARalpha with its modulators. This study uncovers the first example of lysine trimethylation on a mammalian non-histone protein that has an important biological consequence. Our finding also provides the evidence for lysine methylation for the family of nuclear receptors for the first time.
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  18. (2006) Tavera-Mendoza L, Wang TT, Lallemant B, Zhang R, Nagai Y, Bourdeau V, Ramirez-Calderon M, Desbarats J, Mader S, White JH. Convergence of vitamin D and retinoic acid signalling at a common hormone response element. EMBO Rep., 7(2):180-5.
    Although 1,25-dihydroxyvitamin D3 (1,25D3) and retinoic acid (RA) have distinct developmental and physiological roles, both regulate the cell cycle. We provide molecular and genomic evidence that their cognate nuclear receptors regulate common genes through everted repeat TGA(C/T)TPyN8PuG(G/T)TCA (ER8) response elements. ER8 motifs were found in the promoters of several target genes of 1,25D3 and/or RA. Notably, an element was characterized in the cyclin-dependent kinase (CDK) inhibitor p19ink4d gene, and 1,25D3- or RA-induced p19INK4D) expression. P19ink4d knockdown together with depletion of p27kip1, another CDK inhibitor regulated by 1,25D3 and RA, rendered cells resistant to ligand-induced growth arrest. Remarkably, p19INK4D-deficient cells showed increased autophagic cell death, which was markedly enhanced by 1,25D3, but not RA, and attenuated by loss of p27KIP1. These results show a limited crosstalk between 1,25D3 and RA signalling by means of overlapping nuclear receptor DNA binding specificities, and uncover a role for p19INK4D in control of cell survival.
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  19.  review article 
    (2006) Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H. International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol. Rev., 58(4):712-25.
    Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RARalpha, RARbeta, and RARgamma), members of the nuclear hormone receptor superfamily. The most important endogenous retinoid is all-trans-retinoic acid. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis, as well as their disorders. This review summarizes the considerable amount of knowledge generated on these receptors.
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  20. (2005) Laganière J, Deblois G, Giguère V. Functional genomics identifies a mechanism for estrogen activation of the retinoic acid receptor alpha1 gene in breast cancer cells. Mol. Endocrinol., 19(6):1584-92.
    The identification of estrogen receptor (ERalpha) target genes is crucial to our understanding of its predominant role in breast cancer. In this study, we used a chromatin immunoprecipitation (ChIP)-cloning strategy to identify ERalpha-regulatory modules and associated target genes in the human breast cancer cell line MCF-7. We isolated 12 transcriptionally active genomic modules that recruit ERalpha and the coactivator steroid receptor coactivator (SRC)-3 to different intensities in vivo. One of the ERalpha-regulatory modules identified is located 3.7 kb downstream of the first transcriptional start site of the RARA locus, which encodes retinoic acid receptor alpha1 (RARalpha1). This module, which includes an estrogen response element (ERE), is conserved between the human and mouse genomes. Direct binding of ERalpha to the ERE was shown using EMSAs, and transient transfections in MCF-7 cells demonstrated that endogenous ERalpha can induce estrogen-dependent transcriptional activation from the module or the ERE linked to a heterologous promoter. Furthermore, ChIP assays showed that the coregulators SRC-1, SRC-3, and receptor-interacting protein 140 are recruited to this intronic module in an estrogen-dependent manner. As expected from previous studies, the transcription factor Sp1 can be detected at the RARA alpha1 promoter by ChIP. However, treatment with estradiol did not influence Sp1 recruitment nor help recruit ERalpha to the promoter. Finally, ablation of the intronic ERE was sufficient to abrogate the up-regulation of RARA alpha1 promoter activity by estradiol. Thus, this study uncovered a mechanism by which ERalpha significantly activates RARalpha1 expression in breast cancer cells and exemplifies the utility of functional genomics strategies in identifying long-distance regulatory modules for nuclear receptors.
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  21. (2004) Kamashev D, Vitoux D, De Thé H. PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J. Exp. Med., 199(8):1163-74.
    PML-RARA was proposed to initiate acute promyelocytic leukemia (APL) through PML-RARA homodimer-triggered repression. Here, we examined the nature of the PML-RARA protein complex and of its DNA targets in APL cells. Using a selection/amplification approach, we demonstrate that PML-RARA targets consist of two AGGTCA elements in an astonishing variety of orientations and spacings, pointing to highly relaxed structural constrains for DNA binding and identifying a major gain of function of this oncogene. PML-RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells. In these cells, we demonstrate that PML-RARA oligomers are complexed to RXR. Directly probing PML-RARA function in APL cells, we found that the differentiation enhancer cyclic AMP (cAMP) boosted transcriptional activation by RA. cAMP also reversed the normal silencing (subordination) of the transactivating function of RXR when bound to RARA or PML-RARA, demonstrating that the alternate rexinoid/cAMP-triggered APL differentiation pathway also activates PML-RARA targets. Finally, cAMP restored both RA-triggered differentiation and PML-RARA transcriptional activation in mutant RA-resistant APL cells. Collectively, our findings directly demonstrate that APL cell differentiation parallels transcriptional activation through PML-RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy.
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  22.  review article 
    (2004) Claessens F, Gewirth DT. DNA recognition by nuclear receptors. Essays Biochem., 40:59-72.
    The nuclear receptors constitute a large family of ligand-inducible transcription factors. The control of many genetic pathways requires the assembly of these nuclear receptors in defined transcription-activating complexes within control regions of ligand-responsive genes. An essential step is the interaction of the receptors with specific DNA sequences, called hormone-response elements (HREs). These response elements position the receptors, and the complexes recruited by them, close to the genes of which transcription is affected. HREs are bipartite elements that are composed of two hexameric core half-site motifs. The identity of the response elements resides in three features: the nucleotide sequence of the two core motif half-sites, the number of base pairs separating them and the relative orientation of the motifs. The DNA-binding domains of nuclear receptors consist of two zinc-nucleated modules and a C-terminal extension. Residues in the first module determine the specificity of the DNA recognition, while residues in the second module are involved in dimerization. Indeed, nuclear receptors bind to their HREs as either homodimers or heterodimers. Depending on the type of receptor, the C-terminal extension plays a role in sequence recognition, dimerization, or both. The DNA-binding domain is furthermore involved in several other functions including nuclear localization, and interaction with transcription factors and co-activators. It is also the target of post-translational modifications. The DNA-binding domain therefore plays a central role, not only in the correct binding of the receptors to the target genes, but also in the control of other steps of the action mechanism of nuclear receptors.
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  23. (2003) Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R. All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat. Struct. Biol., 10(10):820-5.
    Retinoids regulate gene expression through binding to the nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). In contrast, no ligands for the retinoic acid receptor-related orphan receptors beta and gamma (ROR beta and gamma) have been identified, yet structural data and structure-function analyses indicate that ROR beta is a ligand-regulated nuclear receptor. Using nondenaturing mass spectrometry and scintillation proximity assays we found that all-trans retinoic acid (ATRA) and several retinoids bind to the ROR beta ligand-binding domain (LBD). The crystal structures of the complex with ATRA and with the synthetic analog ALRT 1550 reveal the binding modes of these ligands. ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action.
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  24. (2003) Shaw N, Elholm M, Noy N. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. J. Biol. Chem., 278(43):41589-92.
    Retinoic acid (RA) modulates transcription of numerous target genes, thereby regulating a myriad of biological processes. It is well established that RA functions by activating retinoic acid receptors (RARs), which, in turn, control cell differentiation, proliferation, and apoptosis. However, perplexing reports of diverse and sometime opposing actions of RA have been published. Hence, while RA induces apoptosis and inhibits cell growth in some settings, it potentiates proliferation and acts as an anti-apoptotic agent in others. These observations raise the possibility that signaling pathways other than RAR may be involved in mediating RA activities. Here we show that RA is a high affinity ligand for another nuclear receptor, namely the orphan receptor peroxisome proliferator-activated receptor (PPAR) beta/delta. We demonstrate that while RA does not activate PPARalpha and PPARgamma, it binds to PPARbeta/delta with nanomolar affinity, modulates the conformation of the receptor, promotes interaction with the coactivator SRC-1, and efficiently activates PPARbeta/delta-mediated transcription. Transcriptional signaling by RA is thus exerted by a dual pathway, providing a rationale for understanding divergent cellular responses to this hormone.
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  25. (2002) Farias EF, Arapshian A, Bleiweiss IJ, Waxman S, Zelent A, Mira-Y-Lopez R. Retinoic acid receptor alpha2 is a growth suppressor epigenetically silenced in MCF-7 human breast cancer cells. Cell Growth Differ., 13(8):335-41.
    Retinoic acid (RA) receptor (RAR) beta2 has been shown to be underexpressed in human breast cancer cells, including MCF-7 cells, and recent reports have suggested that hypermethylation of the RAR beta2 promoter and 5'-UTR is the underlying cause. Here we show that RAR alpha2 is also underexpressed in MCF-7 breast cancer cells, at both the message and the protein level, relative to normal or nontumorigenic breast epithelial cells. Bisulfite sequencing of the CpG island in the RAR alpha2 promoter revealed highly penetrant and uniform cytosine methylation in MCF-7 cells. Pretreatment with the DNA methyltransferase inhibitor, azacytidine, followed by treatment with RA and a histone deacetylase inhibitor, trichostatin A, resulted in partial promoter demethylation and RAR alpha2 induction, which strongly suggested that promoter hypermethylation is responsible for RAR alpha2 underexpression. We compared the outcome of ectopic expression in MCF-7 cells of matched levels of RAR alpha2 and RAR beta2. On the basis of a clonogenic assay, RAR alpha2 displayed ligand-dependent growth-suppressive activity similar to that of RARb eta2; thus, 10 and 20 nM RA inhibited clonogenic growth by 52 and 80%, respectively, in RAR alpha2-transfected cells compared with 75 and 77%, respectively, in RAR beta2-transfected cells. We conclude that the silencing of the RAR alpha2 promoter by hypermethylation may play a contributory role in the dysregulation of RA signaling in mammary tumorigenesis.
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  26.  review article 
    (2002) McKenna NJ, O'Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell, 108(4):465-74.
    The nuclear receptor (NR) superfamily of transcription factors regulates gene expression in response to endocrine signaling, and recruitment of coregulators affords these receptors considerable functional flexibility. We will place historical aspects of NR research in context with current opinions on their mechanism of signal transduction, and we will speculate upon future trends in the field.
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  27. (2001) Khorasanizadeh S, Rastinejad F. Nuclear-receptor interactions on DNA-response elements. Trends Biochem. Sci., 26(6):384-90.
    Nuclear receptors regulate transcription by binding to DNA-response elements using their conserved DNA-binding domains. These response elements contain conserved hexameric sequences that can be arranged in various bipartite configurations, including inverted and direct repeats. A series of structural studies on receptor--DNA binding complexes illustrate the strategies used by receptors to recognize the symmetry of their binding site as well as its sequence. These structures also indicate how cooperation between receptors enhances their joint affinity and selectivity for correctly configured sites.
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  28. (2001) Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science, 294(5548):1866-70.
    Cholesterol, fatty acids, fat-soluble vitamins, and other lipids present in our diets are not only nutritionally important but serve as precursors for ligands that bind to receptors in the nucleus. To become biologically active, these lipids must first be absorbed by the intestine and transformed by metabolic enzymes before they are delivered to their sites of action in the body. Ultimately, the lipids must be eliminated to maintain a normal physiological state. The need to coordinate this entire lipid-based metabolic signaling cascade raises important questions regarding the mechanisms that govern these pathways. Specifically, what is the nature of communication between these bioactive lipids and their receptors, binding proteins, transporters, and metabolizing enzymes that links them physiologically and speaks to a higher level of metabolic control? Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.
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  29. (2000) Plassat J, Penna L, Chambon P, Rochette-Egly C. The conserved amphipatic alpha-helical core motif of RARgamma and RARalpha activating domains is indispensable for RA-induced differentiation of F9 cells. J. Cell. Sci., 113 ( Pt 16):2887-95.
    In monolayers cultures, retinoic acid (RA) induces the differentiation of F9 embryonal carcinomal (EC) cells into primitive endoderm-like cells, while a combination of RA and dibutyryl cAMP leads to parietal endoderm-like differentiation. Knock out of all RARgamma isoforms (RARgamma(-/-) line) drastically impairs primitive and subsequent parietal endodermal differentiation and affects the induction of many endogenous RA-responsive genes. Using lines that reexpress RARgamma2 or overexpress RARalpha1 lacking their AF-2AD core (RARgammadeltaAF2 and RARalphadeltaAF2, respectively), we show that this conserved amphipatic alpha-helical motif (helix 12) of the ligand binding domain, and therefore the activation function AF-2 of both receptors, is required for the induction of differentiation and target gene expression upon RA treatment of F9 EC cells. We also show that these deletion mutants behave as dominant negatives.
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  30. (1998) Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature, 391(6669):811-4.
    Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.
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  31.  review article 
    (1996) Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J., 10(9):940-54.
    Retinoids play an important role in development, differentiation, and homeostasis. The discovery of retinoid receptors belonging to the superfamily of nuclear ligand-activated transcriptional regulators has revolutionized our molecular understanding as to how these structurally simple molecules exert their pleiotropic effects. Diversity in the control of gene expression by retinoid signals is generated through complexity at different levels of the signaling pathway. A major source of diversity originates from the existence of two families of retinoid acid (RA) receptors (R), the RAR isotypes (alpha, beta, and gamma) and the three RXR isotypes (alpha, beta, and gamma), and their numerous isoforms, which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. The possibility of cross-modulation (cross-talk) with cell-surface receptors signaling pathways, as well as the finding that RARs and RXRs interact with multiple putative coactivators and/or corepressors, generates additional levels of complexity for the array of combinatorial effects that underlie the pleiotropic effects of retinoids. This review focuses on recent developments, particularly in the area of structure-function relationships.
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  32. (1995) van der Leede BJ, Folkers GE, van den Brink CE, van der Saag PT, van der Burg B. Retinoic acid receptor alpha 1 isoform is induced by estradiol and confers retinoic acid sensitivity in human breast cancer cells. Mol. Cell. Endocrinol., 109(1):77-86.
    Retinoic acid (RA) inhibits proliferation of estrogen receptor (ER)-positive human breast cancer cells, but not the growth of ER-negative cells. We have shown previously that ER-positive cells express higher levels of retinoic acid receptor (RAR) alpha, suggesting that RAR alpha gene expression may be regulated in breast cancer cells by estrogens. We here report that estradiol (E2) increases RAR alpha mRNA in a time- and concentration-dependent manner resulting in a marked increase in RAR alpha protein expression, and present evidence that RAR alpha 1 is the only known isoform of RAR alpha regulated by E2 in breast cancer cells. In parallel we demonstrate that ER-positive cells exhibit greater RA sensitivity in the presence of E2, suggesting that E2-induced expression of RAR alpha 1 is involved in growth inhibition by RA. To directly investigate the role of RAR alpha 1 in RA-mediated growth inhibition, we introduced RAR alpha 1 expression vectors into RA-resistant and ER-negative MDA-MB-231 cells. The RAR alpha 1-transfected cells were growth inhibited by RA, while mock- and untransfected cells were unresponsive. Together, our data indicate that adequate levels of RAR alpha 1, either generated by introduction of expression vectors or endogenously induced by estrogens, are required for growth inhibition of breast cancer cells by RA.
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  33. (1994) Zechel C, Shen XQ, Chambon P, Gronemeyer H. Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements. EMBO J., 13(6):1414-24.
    We have previously reported that the binding site repertoires of heterodimers formed between retinoid X receptor (RXR) and either retinoic acid receptor (RAR) or thyroid hormone receptor (TR) bound to response elements consisting of directly repeated PuG(G/T)TCA motifs spaced by 1-5 bp [direct repeat (DR) elements 1-5] are highly similar to those of their corresponding DNA binding domains (DBDs). We have now mapped the dimerization surfaces located in the DBDs of RXR, RAR and TR, which are responsible for cooperative interaction on DR4 (RXR and TR) and DR5 (RXR and RAR). The D-box of the C-terminal CII finger of RXR provides one of the surfaces which is specifically required for the formation of the heterodimerization interfaces on both DR4 and DR5. Heterodimerization with the RXR DBD on DR5 specifically requires the tip of the RAR CI finger as the complementary surface, while a 7 amino acid sequence encompassing the 'prefinger region', but not the TR CI finger, is specifically required for efficient dimerization of TR and RXR DBDs on DR4. Importantly, DBD swapping experiments demonstrate not only that the binding site repertoires of the full-length receptors are dictated by those of their DBDs, but also that the formation of distinct dimerization interfaces between the DBDs are the critical determinants for cooperative DNA binding of these receptors to specific DRs.
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  34. (1994) Predki PF, Zamble D, Sarkar B, Giguère V. Ordered binding of retinoic acid and retinoid-X receptors to asymmetric response elements involves determinants adjacent to the DNA-binding domain. Mol. Endocrinol., 8(1):31-9.
    Retinoic acid, a pleiotropic regulator of development and homeostasis, controls the expression of specific gene networks via direct interactions with nuclear receptors. The retinoic acid receptor (RAR), as a heterodimer with the retinoid-x receptor (RXR), binds to DNA recognition sites, referred to as retinoic acid response elements (RAREs), that are generally composed of a direct repeat of the half-site core motif PuGGTCA spaced by 2 (DR-2) or 5 (DR-5) basepairs. The asymmetric nature of direct repeat RAREs suggests that RAR and RXR bind preferentially to one of the two half-site core motifs. Here we show that RXR occupies the 5'-up-stream half-site, and RAR the 3'-down-stream half-site of the direct repeat in both DR-2 and DR-5 RAREs. We also demonstrate that a region adjacent to the zinc finger region of RAR and RXR is essential for specific and cooperative binding of DNA-binding domain peptides to RAREs. However, differential utilization of these determinants mediate RAR-RXR heterodimer binding to DR-2 and DR-5 RAREs. The demonstration of ordered but nonequivalent binding of RAR-RXR complexes to DR-2 and DR-5 RAREs sets a precedent for the generation of sequence specificities in heterodimeric DNA-binding proteins.
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  35. (1994) Zechel C, Shen XQ, Chen JY, Chen ZP, Chambon P, Gronemeyer H. The dimerization interfaces formed between the DNA binding domains of RXR, RAR and TR determine the binding specificity and polarity of the full-length receptors to direct repeats. EMBO J., 13(6):1425-33.
    Heterodimers of retinoid X receptor (RXR) and retinoic acid receptor (RAR) bind preferentially to directly repeated elements with spacing of two (DR2) or five (DR5) base pairs, due to the specific heterocooperative interaction of their DNA binding domains (DBDs) on these elements. We have demonstrated in the accompanying paper that the heterodimeric DBD interface that is responsible for the cooperative binding to DR5 elements, specifically involves the D-box of the RXR CII finger and the tip of the RAR CI finger. We show here that a second type of dimerization interface, which specifically implicates the RAR T-box and the RXR CII finger to the exclusion of the D-box, determines the selective binding to DR2 elements. Interestingly, the same type of dimerization interface (RXR T-box and CII finger) is responsible for the cooperative binding of homodimers of the RXR DBD to DR1 elements. Based on the three-dimensional structure of the glucocorticoid receptor DBD, modeling of RXR/RAR, RXR/TR and RXR/RXR DBD cooperative interactions predicts that in all cases the DBD contributing the CII finger, i.e. that of RXR, has to be positioned 5' to its cooperatively bound partner. This binding polarity of the DBDs is conferred upon the full-length receptors, since crosslinking experiments indicate that RXR is always 5' to RAR in complexes between either DR5 or DR2 and RXR/RAR heterodimers. The possible significance of these observations for transactivation by retinoic acid receptors is discussed.
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  36. (1993) Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub MP, LeMeur M, Chambon P. High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc. Natl. Acad. Sci. U.S.A., 90(15):7225-9.
    Retinoic acid (RA) plays a critical role in normal development, growth, and maintenance of certain tissues. The action of RA is thought to be mediated in part by the three nuclear receptors (RAR alpha, -beta, and -gamma), each of which is expressed as multiple isoforms. To investigate the function of the RAR alpha gene, we have disrupted, in the mouse, the whole gene or the isoform RAR alpha 1. Although RAR alpha 1 is the predominant isoform and is highly conserved among vertebrates, RAR alpha 1-null mice appeared normal. However, targeted disruption of the whole RAR alpha gene resulted in early postnatal lethality and testis degeneration. These results, showing that RAR alpha is indeed involved in the transduction of the RA signal, also suggest an unexpected genetic redundancy.
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  37. (1993) Tini M, Otulakowski G, Breitman ML, Tsui LC, Giguère V. An everted repeat mediates retinoic acid induction of the gamma F-crystallin gene: evidence of a direct role for retinoids in lens development. Genes Dev., 7(2):295-307.
    The vertebrate lens is a classical system for examining mechanisms of tissue determination and differentiation, yet little is known about the signaling molecules controlling its development. Here, we report that retinoic acid (RA), a substance known for its teratogenic effects on the eye and as a natural endogenous morphogenetic agent, acts as a regulator of gene expression in the lens. We have identified a novel type of RA response element (RARE) within the lens-specific mouse gamma F-crystallin promoter, consisting of two (A/G)GGTCA motifs in an everted arrangement spaced by 8 nucleotides. This element (gamma F-RARE) mediates activation of the gamma F-crystallin promoter by ligand-activated endogenous lens cell RA receptors (RARs) and confers RA responsiveness when linked to a heterologous promoter. gamma F-RARE is bound in vitro by RAR/RXR heterodimers, and both receptors cooperate in vivo to trans-activate this element. These observations demonstrate a direct effect of RA on lens-specific gene expression and reveal a novel role for retinoids in the development and homeostasis of the mammalian eye.
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  38. (1993) Li E, Sucov HM, Lee KF, Evans RM, Jaenisch R. Normal development and growth of mice carrying a targeted disruption of the alpha 1 retinoic acid receptor gene. Proc. Natl. Acad. Sci. U.S.A., 90(4):1590-4.
    Three unlinked genes encode receptors for retinoic acid (RAR alpha, -beta, and -gamma). Each gene expresses two major protein isoforms differing in the amino terminal A domain by alternative promoter use, fused to common exons encoding most of the receptor protein. The two RAR alpha transcripts (RAR alpha 1 and -alpha 2) are differentially expressed and evolutionarily conserved, as are the RAR beta and -gamma transcripts, suggesting that each isoform may have specific functions in the development of animals. To address the biological function of the alpha 1 receptor, we have disrupted the portion of the RAR alpha gene encoding this isoform by homologous recombination in mouse embryonic stem cells. Surprisingly, offspring homozygous for this mutation were viable and showed no apparently altered phenotype. RNA analysis confirmed that the RAR alpha 1 transcript was absent in homozygous tissues, and no evidence for a compensatory increase of RAR alpha 2 or of another RAR gene was obtained to account for the vitality of the mutant animals. These results clearly demonstrate that loss of RAR alpha 1 function does not disrupt embryonic development and argue for combinatorial or overlapping functions among the RAR isoforms.
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  39. (1992) Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature, 355(6359):446-9.
    Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. RAR and RXR have a high degree of cooperativity in binding to target DNA, consistent with previous reports indicating that the binding of either RAR or RXR to their cognate response elements is enhanced by factors present in nuclear extracts. RXR also interacts directly with and enhances the binding of nuclear receptors conferring responsiveness to vitamin D3 and thyroid hormone T3; the DNA-binding activities of these receptors are also stimulated by the presence of nuclear extracts. Together these data indicate that RXR has a central role in multiple hormonal signalling pathways.
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  40. (1992) Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, Evans RM. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev., 6(3):329-44.
    An understanding of the differences and similarities of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) systems requires knowledge of the diversity of their family members, their patterns of expression, and their pharmacological response to ligands. In this paper we report the isolation of a family of mouse RXR genes encoding three distinct receptors (RXR alpha, beta, and gamma). They are closely related to each other in their DNA- and ligand-binding domains but are quite divergent from the RAR subfamily in both structure and ligand specificity. Recently, we demonstrated that all-trans retinoic acid (RA) serves as a "pro-hormone" to the isomer 9-cis RA, which is a high-affinity ligand for the human RXR alpha. We extend those findings to show that 9-cis RA is also "retinoid X" for mouse RXR alpha, beta, and gamma. Trans-activation analyses show that although all three RXRs respond to a variety of endogenous retinoids, 9-cis RA is their most potent ligand and is up to 40-fold more active than all-trans RA. Northern blot and in situ hybridization analyses define a broad spectrum of expression for the RXRs, which display unique patterns and only partially overlap themselves and the RARs. This study suggests that the RXR family plays critical roles in diverse aspects of development, from embryo implantation to organogenesis and central nervous system differentiation, as well as in adult physiology.
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  41. (1991) Leroy P, Krust A, Zelent A, Mendelsohn C, Garnier JM, Kastner P, Dierich A, Chambon P. Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid. EMBO J., 10(1):59-69.
    Together with the previously described mouse retinoic acid receptor alpha-1 (mRAR-alpha 1, formerly mRAR-alpha 0), we have isolated and characterized here a total of seven mRAR-alpha cDNA isoforms (mRAR-alpha 1 to alpha 7). These isoforms are generated from mRAR-alpha primary transcript(s) of a single gene by alternative splicing of at least eight different exons with the exon which encodes the amino acid sequence of their common B region. All of these isoforms differ in their 5'-untranslated regions (5'-UTRs) and, in the case of mRAR-alpha 1 and alpha 2, also in the sequences encoding the N-terminal A region which is known to be important for differential trans-activation by other members of the nuclear receptor superfamily. In addition, the sequences encoding the open reading frames (ORFs) of mRAR-alpha 3 and alpha 4 cDNA isoforms remain open to their very 5' ends, which suggests that these two isoforms may also encode RAR-alpha s with unique A region amino acid sequences. The two predominant isoforms, mRAR-alpha 1 and alpha 2, were found to be differentially expressed in mouse adult and fetal tissues, as well as in P19 and F9 embryonal carcinoma (EC) cell lines. Interestingly, the expression of mRAR-alpha 2, in contrast to that of the mRAR-alpha 1 isoform, was induced by retinoic acid (RA) in EC cells, thus suggesting the presence of two promoters in the 5' region of the mRAR-alpha gene, which differ in their response to RA. The conservation between mouse and human RAR-alpha 1 and alpha 2 cDNA isoform sequences, as seen by cross-hybridization in Southern blots or by DNA sequence analysis, together with their differential patterns of expression, strongly suggests that they perform specific functions during embryogenesis and in the adult.
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