An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway

doi:10.1016/S0092-8674(00)80900-9

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An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway

Journal Article•DOI•

An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway

Steven A. Kliewer¹, John T. Moore¹, Laura E. Wade¹, Jeff L. Staudinger¹, Michael A. Watson¹, Stacey A. Jones¹, David D. McKee¹, Beverly B. Oliver¹, Timothy M. Willson¹, Rolf Zetterström², Thomas Perlmann³, Jürgen M. Lehmann¹ - Show less +8 more•Institutions (3)

Research Triangle Park¹, Karolinska Institutet², Ludwig Institute for Cancer Research³

09 Jan 1998-Cell (Cell Press)-Vol. 92, Iss: 1, pp 73-82

TL;DR: The results provide evidence for the existence of a novel steroid hormone signaling pathway with potential implications in the regulation of steroid hormone and sterol homeostasis and the expression of the CYP3A family of steroid hydroxylases and modulates sterol and bile acid biosynthesis in vivo.

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About: This article is published in Cell.The article was published on 1998-01-09 and is currently open access. It has received 1493 citations till now. The article focuses on the topics: Steroid hormone & Nuclear receptor.

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Journal Article•DOI•

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

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Robert M. Sapolsky¹, L. Michael Romero², Allan Munck³•Institutions (3)

Stanford University¹, Tufts University², Dartmouth College³

01 Feb 2000-Endocrine Reviews

TL;DR: This review considers recent findings regarding GC action and generates criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor.

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Abstract: The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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6,707 citations

Cites background from "An Orphan Nuclear Receptor Activate..."

...For example, some genomic steroid hormone actions may be mediated by as yet physiologically uncharacterized nuclear receptors (330)....
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Journal Article•DOI•

The PPARs: from orphan receptors to drug discovery.

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Timothy M. Willson¹, Peter Brown¹, Daniel D. Sternbach¹, Brad R. Henke¹•Institutions (1)

Research Triangle Park¹

24 Feb 2000-Journal of Medicinal Chemistry

1,775 citations

Journal Article•DOI•

A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis

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Bryan Goodwin¹, Stacey A. Jones², Roger R. Price², Michael A. Watson², D.D. McKee², Linda B. Moore², Cristin M. Galardi², Joan G. Wilson², Michael C. Lewis², Matthew E. Roth, Patrick R. Maloney², Timothy M. Willson¹, Steven A. Kliewer¹ - Show less +9 more•Institutions (2)

Research Triangle Park¹, GlaxoSmithKline²

01 Sep 2000-Molecular Cell

TL;DR: A potent, nonsteroidal FXR ligand is used to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain that provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.

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1,717 citations

Journal Article•DOI•

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.

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Jürgen M. Lehmann¹, David D. McKee, Michael A. Watson, Timothy M. Willson, John T. Moore, Steven A. Kliewer - Show less +2 more•Institutions (1)

Research Triangle Park¹

01 Sep 1998-Journal of Clinical Investigation

TL;DR: The identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP 3A4 expression is reported.

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Abstract: The cytochrome P-450 monooxygenase 3A4 (CYP3A4) is responsible for the oxidative metabolism of a wide variety of xenobiotics including an estimated 60% of all clinically used drugs. Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients, has remained unclear. We report the identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP3A4 expression. Comparison of hPXR with the recently cloned mouse PXR reveals marked differences in their activation by certain drugs, which may account in part for the species-specific effects of compounds on CYP3A gene expression. These findings provide a molecular explanation for the ability of disparate chemicals to induce CYP3A4 levels and, furthermore, provide a basis for developing in vitro assays to aid in predicting whether drugs will interact in humans.

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1,551 citations

Cites background or methods from "An Orphan Nuclear Receptor Activate..."

...We also tested several naturally occurring C21 steroids on hPXR that were previously shown to activate mPXR1 (7)....
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...Both hPXR and mPXR1 bind efficiently as heterodimers with RXR to the DR3- and ER6-type PXREs that are crucial in the regulation of the CYP3A1 and CYP3A4 genes, respectively....
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...Interestingly, this half-site configuration is very different from that found in the CYP3A1 PXR response element (PXRE), which is composed of two half-sites organized as a direct repeat (DR) with a three nucleotide spacer, a DR3 motif (7)....
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...We recently provided several lines of evidence that mPXR1 regulates CYP3A1 gene expression: mPXR1 was activated by compounds known to activate CYP3A1 gene expression including glucocorticoids and antiglucocorticoids; mPXR1 and CYP3A1 gene expression colocalized in the liver and small intestine; and mPXR1 bound to a response element in the CYP3A1 gene promoter that had been determined previously to confer responsiveness to glucocorticoids and antiglucocorticoids (7, 12, 13)....
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...However, transfection experiments performed in CV-1 cells with the hPXR clone and a reporter plasmid containing four copies of an established mPXR binding site from the rat CYP3A1 gene promoter inserted upstream of the minimal thymidine kinase (tk) promoter and the chloramphenicol acetyltransferase (CAT) gene (7) demonstrated that the hPXR clone encoded a functional nuclear receptor that was activated efficiently by dexamethasone-t-butylacetate, a known mPXR1 ligand (7; Fig....
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Journal Article•DOI•

Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.

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Haibo Wang¹, Jasmine Chen², Kevin Hollister², Lawrence C. Sowers¹, Barry M. Forman² - Show less +1 more•Institutions (2)

City of Hope National Medical Center¹, Beckman Research Institute²

01 May 1999-Molecular Cell

TL;DR: It is suggested that FXR (BAR) is the endogenous biliary component that selectively activates the orphan nuclear receptor, FXR, and thus an important regulator of cholesterol homeostasis.

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1,445 citations

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References

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Journal Article•DOI•

The steroid and thyroid hormone receptor superfamily

[...]

Ronald M. Evans¹•Institutions (1)

Salk Institute for Biological Studies¹

13 May 1988-Science

TL;DR: A superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid is identified, suggesting mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.

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Abstract: Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.

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7,493 citations

"An Orphan Nuclear Receptor Activate..." refers background in this paper

...…hormone These related proteins lack identified ligands and, as asignaling pathway with potential implications in the consequence, have been termed orphan nuclear recep-regulation of steroid hormone and sterol homeostasis. tors (Evans, 1988; Mangelsdorf and Evans, 1995; Enmark and Gustafsson, 1996)....
[...]
...Recep- tors for each of the major classes of sex and adrenal ceptors (Forman et al., 1997; Kliewer et al., 1997; Krey steroids have been characterized (Evans, 1988; Beato et al., 1997), retinoids and farnesoids as activators of et al., 1995; Mangelsdorf et al., 1995)....
[...]
...…hormone receptors †Department of Molecular Sciences revealed that they comprise a subfamily within a larger ‡Department of Medicinal Chemistry superfamily of structurally related proteins (Evans, 1988; Glaxo Wellcome Research and Development Mangelsdorf and Evans, 1995; Mangelsdorf et al., 1995)....
[...]

Journal Article•DOI•

The nuclear receptor superfamily: the second decade.

[...]

David J. Mangelsdorf¹, Carl S. Thummel², Miguel Beato, Peter Herrlich³, Günther Schütz, Kazuhiko Umesono, Bruce Blumberg⁴, Philippe Kastner⁵, Manuel Mark⁵, Pierre Chambon⁵, Ronald M. Evans⁴ - Show less +7 more•Institutions (5)

University of Texas Southwestern Medical Center¹, University of Utah², Karlsruhe Institute of Technology³, Salk Institute for Biological Studies⁴, Centre national de la recherche scientifique⁵

15 Dec 1995-Cell

TL;DR: This research presents a new probabilistic procedure called ‘spot-spot analysis’ to characterize the response of the immune system to the presence of E.coli.

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6,818 citations

"An Orphan Nuclear Receptor Activate..." refers background in this paper

...The nonsteroid S-171 77 Stockholm receptors differ from their steroid hormone receptor Sweden counterparts in several respects (Mangelsdorf and Evans, ‖The Ludwig Institute for Cancer Research 1995; Mangelsdorf et al., 1995)....
[...]
...Recep- tors for each of the major classes of sex and adrenal ceptors (Forman et al., 1997; Kliewer et al., 1997; Krey steroids have been characterized (Evans, 1988; Beato et al., 1997), retinoids and farnesoids as activators of et al., 1995; Mangelsdorf et al., 1995)....
[...]
...…hormone receptors †Department of Molecular Sciences revealed that they comprise a subfamily within a larger ‡Department of Medicinal Chemistry superfamily of structurally related proteins (Evans, 1988; Glaxo Wellcome Research and Development Mangelsdorf and Evans, 1995; Mangelsdorf et al., 1995)....
[...]

Journal Article•DOI•

An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ)

[...]

Jürgen M. Lehmann¹, Linda B. Moore¹, Tracey Smith-Oliver¹, William O. Wilkison¹, Timothy M. Willson¹, Steven A. Kliewer² - Show less +2 more•Institutions (2)

GlaxoSmithKline¹, Research Triangle Park²

02 Jun 1995-Journal of Biological Chemistry

TL;DR: It is reported that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily recently shown to function in adipogenesis, and raised the intriguing possibility that PPARγ is a target for the therapeutic actions of this class of compounds.

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3,635 citations

"An Orphan Nuclear Receptor Activate..." refers background or methods in this paper

...Interestingly, we found that the activity of the GAL4PXR.1 chimera was markedly induced by 10 mM concentrations of a variety of synthetic steroids including the glucocorticoids dexamethasone, dexamethasone-tbutyl-acetate, and dexamethasone-21-acetate, and the pregnenolone derivative 6,16a-dimethyl pregnenolone (Figure 3B)....
[...]
...The (UAS)5-tk-CAT reporter plas-PXR is activated by pregnenolone and its metabolites mid has been previously described (Lehmann et al., 1995)....
[...]
...…of PXR is distinct from any of the other steroid prepared and assayed for CAT and b-galactosidase activities as hormone receptors identified to date, suggesting that described previously (Lehmann et al., 1995). this orphan receptor defines a novel endocrine signaling Northern Analysispathway....
[...]
...(C and D) of the GR. High power bright-field microscopy showing the abundance of silver Notably, the GAL4-PXR.2 chimera displayed a much grains in the liver (C) and in the intestine (D) where mRNA labeling more restricted activation profile....
[...]
...Elements Present in the CYP3A1 and CYP3A2 Gene Promoters(B) CV-1 cells were cotransfected with expression plasmids encod- (A) Alignment of DR-3 motifs present in the promoter regions of theing either GAL4-PXR.1 (filled bars) or GAL4-PXR.2 (open bars) and CYP3A1 and CYP3A2 genes....
[...]

Journal Article•DOI•

The RXR heterodimers and orphan receptors

[...]

David J. Mangelsdorf¹, Ronald M. Evans²•Institutions (2)

University of Texas Southwestern Medical Center¹, Salk Institute for Biological Studies²

15 Dec 1995-Cell

TL;DR: The historical links between the steroid and nonsteroid receptor signaling systems are established, the explosive development of the retinoid X receptor (RXR) heterodimer and orphan receptor family is charted, the impact of these discoveries on the authors' understanding of the mechanisms of hormonal signaling is explained, and emerging issues and implications are presented.

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3,190 citations

"An Orphan Nuclear Receptor Activate..." refers background in this paper

...…receptors generally bind to their HREs as homodimers, most of the nonsteroid hormone receptors Summary identified to date bind to DNA as heterodimers with the 9-cis retinoic acid receptors (RXRs) (Glass, 1994; Steroid hormones exert profound effects on differenti- Mangelsdorf and Evans, 1995)....
[...]
...…hormone receptors †Department of Molecular Sciences revealed that they comprise a subfamily within a larger ‡Department of Medicinal Chemistry superfamily of structurally related proteins (Evans, 1988; Glaxo Wellcome Research and Development Mangelsdorf and Evans, 1995; Mangelsdorf et al., 1995)....
[...]
...*Department of Molecular Endocrinology The molecular cloning of steroid hormone receptors †Department of Molecular Sciences revealed that they comprise a subfamily within a larger ‡Department of Medicinal Chemistry superfamily of structurally related proteins (Evans, 1988; Glaxo Wellcome Research and Development Mangelsdorf and Evans, 1995; Mangelsdorf et al., 1995)....
[...]
...…hormone These related proteins lack identified ligands and, as asignaling pathway with potential implications in the consequence, have been termed orphan nuclear recep-regulation of steroid hormone and sterol homeostasis. tors (Evans, 1988; Mangelsdorf and Evans, 1995; Enmark and Gustafsson, 1996)....
[...]
...Thus, bothas heterodimers with RXR (Umesono et al., 1991; Smith et al., 1994; Mangelsdorf and Evans, 1995), we postu- PXR isoforms can bind specifically as heterodimers with RXRa to DR-3 motifs found in the promoter regions oflated that PXR might bind to the CYP3A1 and CYP3A2 DR-3 motifs as a…...
[...]

Journal Article•DOI•

Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily

[...]

Sergio A. Onate¹, Sophia Y. Tsai¹, Ming-Jer Tsai¹, Bert W. O'Malley¹•Institutions (1)

Baylor College of Medicine¹

24 Nov 1995-Science

TL;DR: Results indicate that SRC-1 encodes a coactivator that is required for full transcriptional activity of the steroid receptor superfamily.

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Abstract: A yeast two-hybrid system was used to identify a protein that interacts with and enhances the human progesterone receptor (hPR) transcriptional activity without altering the basal activity of the promoter. Because the protein stimulated transactivation of all the steroid receptors tested, it has been termed steroid receptor coactivator-1 (SRC-1). Coexpression of SRC-1 reversed the ability of the estrogen receptor to squelch activation by hPR. Also, the amino terminal truncated form of SRC-1 acted as a dominant-negative repressor. Together, these results indicate that SRC-1 encodes a coactivator that is required for full transcriptional activity of the steroid receptor superfamily.

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2,399 citations