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Endocrine Reviews 20 (5): 689
Copyright © 1999 by The Endocrine Society

Orphan Nuclear Receptors: From Gene to Function1

Vincent Giguère

Molecular Oncology Group, McGill University Health Centre and Departments of Biochemistry, Medicine, and Oncology, McGill University, Montréal, Québec, Canada H3A 1A1

I. Introduction
II. Nuclear Receptors: General Concepts
A. Anatomy of nuclear receptors
B. Mechanisms of action
III. Orphan Nuclear Receptors
A. Definition
B. Nomenclature
C. Structural and functional diversity
IV. Novel Hormone Response Systems: RXR and Its Heterodimeric Partners
A. RXR: rexinoids
B. PPAR: multiple ligands, multiple functions
C. PXR: pregnanes, xenobiotic compounds, and benzoate derivatives
D. CAR (constitutive androstane receptor): androstanes and phenobarbital
E. LXR: control of cholesterol metabolism by oxysterols
F. FXR: bile acids receptor
V. Orphans in Search of a Home
A. HNF4: diabetes and possible regulation by acyl-coenzyme A (CoA) thioesters
B. FTZ-F1: steroidogenesis and sexual development
C. Rev-Erb: singular members of the superfamily
D. ROR: neuron development and T cell selection
E. TR2: the testis receptors
F. TLX: forebrain development
G. COUP-TF: neurogenesis, angiogenesis, and heart development
H. ERR: placenta development and control of lipid metabolism
I. NGFI-B: hypothalamus-pituitary axis (HPA), T cells, and dopaminergic neurons
J. GCNF: one of a kind
K. DAX-1: adrenal development and sex determination
L. SHP: a promiscuous and inhibitory heterodimeric partner
VI. Concluding Remarks




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Y.-Y. Park, H.-J. Kim, J.-Y. Kim, M.-Y. Kim, K.-H. Song, K. Cheol Park, K.-Y. Yu, M. Shong, K.-H. Kim, and H.-S. Choi
Differential Role of the Loop Region between Helices H6 and H7 within the Orphan Nuclear Receptors Small Heterodimer Partner and DAX-1
Mol. Endocrinol., May 1, 2004; 18(5): 1082 - 1095.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Laganiere, G. B. Tremblay, C. R. Dufour, S. Giroux, F. Rousseau, and V. Giguere
A Polymorphic Autoregulatory Hormone Response Element in the Human Estrogen-related Receptor {alpha} (ERR{alpha}) Promoter Dictates Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} Control of ERR{alpha} Expression
J. Biol. Chem., April 30, 2004; 279(18): 18504 - 18510.
[Abstract] [Full Text] [PDF]

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 Genome ResHome page
Z. Zhang, P. E. Burch, A. J. Cooney, R. B. Lanz, F. A. Pereira, J. Wu, R. A. Gibbs, G. Weinstock, and D. A. Wheeler
Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome
Genome Res., April 1, 2004; 14(4): 580 - 590.
[Abstract] [Full Text] [PDF]

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 Arterioscler. Thromb. Vasc. Bio.Home page
F. Boukhtouche, J. Mariani, and A. Tedgui
The "CholesteROR" Protective Pathway in the Vascular System
Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 637 - 643.
[Abstract] [Full Text] [PDF]

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 Arterioscler. Thromb. Vasc. Bio.Home page
J. Rius, J. Martinez-Gonzalez, J. Crespo, and L. Badimon
Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB
Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 697 - 702.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
E. Nsegbe, A. Wallen-Mackenzie, S. Dauger, J.-C. Roux, Y. Shvarev, H. Lagercrantz, T. Perlmann, and E. Herlenius
Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice
J. Physiol., April 1, 2004; 556(1): 43 - 59.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
T. Tokumoto, M. Tokumoto, R. Horiguchi, K. Ishikawa, and Y. Nagahama
Diethylstilbestrol induces fish oocyte maturation
PNAS, March 9, 2004; 101(10): 3686 - 3690.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. H. Bassett, T. Suzuki, H. Sasano, P. C. White, and W. E. Rainey
The Orphan Nuclear Receptors NURR1 and NGFIB Regulate Adrenal Aldosterone Production
Mol. Endocrinol., February 1, 2004; 18(2): 279 - 290.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. Galleguillos, A. Vecchiola, J. A. Fuentealba, V. Ojeda, K. Alvarez, A. Gomez, and M. E. Andres
PIAS{gamma} Represses the Transcriptional Activation Induced by the Nuclear Receptor Nurr1
J. Biol. Chem., January 16, 2004; 279(3): 2005 - 2011.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
Y. Chen, L.-N. Wei, and J. D. Muller
Probing protein oligomerization in living cells with fluorescence fluctuation spectroscopy
PNAS, December 23, 2003; 100(26): 15492 - 15497.
[Abstract] [Full Text] [PDF]

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 Genes Dev.Home page
A. Wallen-Mackenzie, A. M. de Urquiza, S. Petersson, F. J. Rodriguez, S. Friling, J. Wagner, P. Ordentlich, J. Lengqvist, R. A. Heyman, E. Arenas, et al.
Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells
Genes & Dev., December 15, 2003; 17(24): 3036 - 3047.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
H.-J. Kim, J.-Y. Kim, Y.-Y. Park, and H.-S. Choi
Synergistic activation of the human orphan nuclear receptor SHP gene promoter by basic helix-loop-helix protein E2A and orphan nuclear receptor SF-1
Nucleic Acids Res., December 1, 2003; 31(23): 6860 - 6872.
[Abstract] [Full Text] [PDF]

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 GeneticsHome page
M. E. Colosimo, S. Tran, and P. Sengupta
The Divergent Orphan Nuclear Receptor ODR-7 Regulates Olfactory Neuron Gene Expression via Multiple Mechanisms in Caenorhabditis elegans
Genetics, December 1, 2003; 165(4): 1779 - 1791.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. Liu, Z. Zhang, W. Gladwell, and C. T. Teng
Estrogen Stimulates Estrogen-Related Receptor {alpha} Gene Expression through Conserved Hormone Response Elements
Endocrinology, November 1, 2003; 144(11): 4894 - 4904.
[Abstract] [Full Text] [PDF]

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 J. Exp. Biol.Home page
M. Wiens, R. Batel, M. Korzhev, and W. E. G. Muller
Retinoid X receptor and retinoic acid response in the marine sponge Suberites domuncula
J. Exp. Biol., September 15, 2003; 206(18): 3261 - 3271.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. Gianni, A. Tarrade, E. A. Nigro, E. Garattini, and C. Rochette-Egly
The AF-1 and AF-2 Domains of RAR{gamma}2 and RXR{alpha} Cooperate for Triggering the Transactivation and the Degradation of RAR{gamma}2/RXR{alpha} Heterodimers
J. Biol. Chem., September 5, 2003; 278(36): 34458 - 34466.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
S. Suzuki, N. Suzuki, C. Mirtsos, T. Horacek, E. Lye, S.-K. Noh, A. Ho, D. Bouchard, T. W. Mak, and W.-C. Yeh
Nur77 as a survival factor in tumor necrosis factor signaling
PNAS, July 8, 2003; 100(14): 8276 - 8280.
[Abstract] [Full Text] [PDF]

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 J. Nutr.Home page
S. A. Kliewer
The Nuclear Pregnane X Receptor Regulates Xenobiotic Detoxification
J. Nutr., July 1, 2003; 133(7): 2444S - 2447.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
P. Ordentlich, Y. Yan, S. Zhou, and R. A. Heyman
Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1
J. Biol. Chem., June 27, 2003; 278(27): 24791 - 24799.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
S. Catalano, V. Pezzi, A. Chimento, C. Giordano, A. Carpino, M. Young, M. J. McPhaul, and S. Ando
Triiodothyronine Decreases the Activity of the Proximal Promoter (PII) of the Aromatase Gene in the Mouse Sertoli Cell Line, TM4
Mol. Endocrinol., May 1, 2003; 17(5): 923 - 934.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
H. Mizusaki, K. Kawabe, T. Mukai, E. Ariyoshi, M. Kasahara, H. Yoshioka, A. Swain, and K.-i. Morohashi
Dax-1 (Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Congenita Critical Region on the X Chromosome, Gene 1) Gene Transcription Is Regulated by Wnt4 in the Female Developing Gonad
Mol. Endocrinol., April 1, 2003; 17(4): 507 - 519.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. N. Schreiber, D. Knutti, K. Brogli, T. Uhlmann, and A. Kralli
The Transcriptional Coactivator PGC-1 Regulates the Expression and Activity of the Orphan Nuclear Receptor Estrogen-Related Receptor alpha (ERRalpha )
J. Biol. Chem., March 7, 2003; 278(11): 9013 - 9018.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
K. Otte, H. Kranz, I. Kober, P. Thompson, M. Hoefer, B. Haubold, B. Remmel, H. Voss, C. Kaiser, M. Albers, et al.
Identification of Farnesoid X Receptor {beta} as a Novel Mammalian Nuclear Receptor Sensing Lanosterol
Mol. Cell. Biol., February 1, 2003; 23(3): 864 - 872.
[Abstract] [Full Text]

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 Circ. Res.Home page
J. Martinez-Gonzalez, J. Rius, A. Castello, C. Cases-Langhoff, and L. Badimon
Neuron-Derived Orphan Receptor-1 (NOR-1) Modulates Vascular Smooth Muscle Cell Proliferation
Circ. Res., January 10, 2003; 92(1): 96 - 103.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
T. Suzuki, M. Kasahara, H. Yoshioka, K.-i. Morohashi, and K. Umesono
LXXLL-Related Motifs in Dax-1 Have Target Specificity for the Orphan Nuclear Receptors Ad4BP/SF-1 and LRH-1
Mol. Cell. Biol., January 1, 2003; 23(1): 238 - 249.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
E. Raspe, G. Mautino, C. Duval, C. Fontaine, H. Duez, O. Barbier, D. Monte, J. Fruchart, J.-C. Fruchart, and B. Staels
Transcriptional Regulation of Human Rev-erbalpha Gene Expression by the Orphan Nuclear Receptor Retinoic Acid-related Orphan Receptor alpha
J. Biol. Chem., December 13, 2002; 277(51): 49275 - 49281.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
L. J. Borgius, K. R. Steffensen, J.-A. Gustafsson, and E. Treuter
Glucocorticoid Signaling Is Perturbed by the Atypical Orphan Receptor and Corepressor SHP
J. Biol. Chem., December 13, 2002; 277(51): 49761 - 49766.
[Abstract] [Full Text] [PDF]

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 J. Lipid Res.Home page
E. Raspe, H. Duez, A. Mansen, C. Fontaine, C. Fievet, J.-C. Fruchart, B. Vennstrom, and B. Staels
Identification of Rev-erb{alpha} as a physiological repressor of apoC-III gene transcription
J. Lipid Res., December 1, 2002; 43(12): 2172 - 2179.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. E. Torres-Padilla, F. M. Sladek, and M. C. Weiss
Developmentally Regulated N-terminal Variants of the Nuclear Receptor Hepatocyte Nuclear Factor 4alpha Mediate Multiple Interactions through Coactivator and Corepressor-Histone Deacetylase Complexes
J. Biol. Chem., November 15, 2002; 277(47): 44677 - 44687.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
S. A. Kliewer, B. Goodwin, and T. M. Willson
The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic Metabolism
Endocr. Rev., October 1, 2002; 23(5): 687 - 702.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
A. N. Moraitis, V. Giguere, and C. C. Thompson
Novel Mechanism of Nuclear Receptor Corepressor Interaction Dictated by Activation Function 2 Helix Determinants
Mol. Cell. Biol., October 1, 2002; 22(19): 6831 - 6841.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
P. Delerive, W. W. Chin, and C. S. Suen
Identification of Reverbalpha as a Novel RORalpha Target Gene
J. Biol. Chem., September 13, 2002; 277(38): 35013 - 35018.
[Abstract] [Full Text] [PDF]

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 J. Leukoc. Biol.Home page
Y.-W. He
Orphan nuclear receptors in T lymphocyte development
J. Leukoc. Biol., September 1, 2002; 72(3): 440 - 446.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. Jung, M. Fried, and G. A. Kullak-Ublick
Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor alpha
J. Biol. Chem., August 16, 2002; 277(34): 30559 - 30566.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
T. M. Willson and J. T. Moore
Minireview: Genomics Versus Orphan Nuclear Receptors--A Half-Time Report
Mol. Endocrinol., June 1, 2002; 16(6): 1135 - 1144.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
F. Gay, P. Barath, C. Desbois-Le Peron, R. Metivier, R. Le Guevel, D. Birse, and G. Salbert
Multiple Phosphorylation Events Control Chicken Ovalbumin Upstream Promoter Transcription Factor I Orphan Nuclear Receptor Activity
Mol. Endocrinol., June 1, 2002; 16(6): 1332 - 1351.
[Abstract] [Full Text] [PDF]


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