Orphan Nuclear Receptors: Shifting Endocrinology into Reverse

Kliewer, Steven A.; Lehmann, J.; Willson, Timothy M.

doi:10.1126/science.284.5415.757

Cited by 466 publications

(304 citation statements)

References 58 publications

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“…The liver is a major target organ for estrogen action, so that the liver-abundant xenobiotic orphan nuclear receptors, CAR, or SXR, have the potential to modulate steroid hormone homeostasis (20). On one level, these nuclear receptors may regulate estrogen action by virtue of their induction of the cytochrome P-450 drug metabolizing enzymes that alter hepatic metabolism of estrogens.…”

Section: Discussionmentioning

confidence: 99%

“…The liver is the major organ that metabolizes steroids and one of the target organs for estrogen action in the body. ER␣ as well as these liver-enriched orphan receptors and their heterodimeric partner RXR are all expressed in the liver (20). Recent studies showed that the p160 coactivators, SRC-1, GRIP-1, and SRC-3, are expressed in the liver (21,22) and play a role in transcriptional activation mediated by the orphan receptors, CAR and SXR (16,23).…”

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confidence: 99%

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Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

Min

Kim

Bae

et al. 2002

Journal of Biological Chemistry

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Estrogen receptor (ER) activity can be modulated by the action of other nuclear receptors. To study whether ER activity is altered by orphan nuclear receptors that mediate the cellular response to xenobiotics, cross-talk between ER and constitutive androstane receptor (CAR), steroid and xenobiotic receptor, or peroxisome proliferator-activated receptor ␥ was examined in HepG2 cells. Of these receptors, CAR substantially inhibited ER-mediated transcriptional activity of the vitellogenin B1 promoter as well as a synthetic estrogen responsive element (ERE)-containing promoter. Treatment with an agonist of CAR, 1,4-bis-(2-(3,5-dichloropyridoxyl))benzene, potentiated CAR-mediated transcriptional repression. In contrast, an antagonist of CAR, androstenol, alleviated the repression effect. Although CAR interacted with the ER in solution, CAR did not interact with the ER bound to the ERE. CAR/retinoid X receptor bound to the ERE but with much lower affinity than ER. Incremental amounts of CAR elicited a progressive reduction of the ER activity induced by the p160 coactivator glucocorticoid receptor interacting protein 1 (GRIP-1). In turn, increasing amounts of GRIP-1 progressively reversed the depression of ER activity by CAR. An agonist or antagonist of CAR potentiated or alleviated, respectively, the CAR-mediated repression of the GRIP-1-enhanced ER activity, which is consistent with the ability of theses ligands to increase or decrease, respectively, the interaction of CAR with GRIP-1. A CAR mutant that did not interact with GRIP-1 did not inhibit ER-mediated transactivation. Our data demonstrate that xenobiotic nuclear receptor CAR antagonizes ER-mediated transcriptional activity by squelching limiting amounts of p160 coactivator and imply that xenobiotics may influence ER function of female reproductive physiology, cell differentiation, tumorigenesis, and lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

Min

Kim

Bae

et al. 2002

Journal of Biological Chemistry

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“…Orphan nuclear receptors are members of the nuclear receptor family that lack identified ligands (27). Recent studies have identified several natural and synthetic ligands for orphan nuclear receptors, which led to new hormone-response systems implicated in the control of various aspects of development and adult physiology (28,29). Among orphan nuclear receptors, the estrogen-related receptors have been reported to be inhibited in their binding with coactivator protein by DES.…”

Section: Discussionmentioning

confidence: 99%

Diethylstilbestrol induces fish oocyte maturation

Tokumoto

Horiguchi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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O ocyte maturation in lower vertebrates is triggered by maturation-inducing hormone (MIH), which acts on receptors located on the oocyte membrane and induces the activation of maturation-promoting factor in the oocyte cytoplasm (1-4). During the course of maturation, oocytes undergo drastic morphological changes associated with progression of the meiotic cell cycle, in which breakdown of the oocyte nuclear envelope [germinal vesicle breakdown (GVBD)] occurring at the prophase͞metaphase transition is usually regarded as a hallmark of the progress of oocyte maturation. Two MIHs, 17␣,20␤-dihydroxy-4-pregnen-3-one (17,20␤-DHP) and 17␣,20␤,21-trihydroxy-4-pregnen-3-one (20␤-S), have been identified in several fish species (5, 6). In goldfish, 17,20␤-DHP has been shown to induce oocyte maturation by stimulating the de novo synthesis of cyclin B, a regulatory subunit of maturationpromoting factor (7). Although progestins including 17,20␤-DHP and 20␤-S are the most potent steroid inducers of oocyte maturation in fish, other hormones such as deoxycorticosterone and testosterone, but not estradiol or its analogs, are also effective (8).Several endocrine-disrupting chemicals, Kepon and dichlorodiphenyldichloroethane, have been reported to antagonize MIH-induced meiotic maturation of fish oocytes in vitro (9). One of the environmental endocrine-disrupting chemicals (EEDCs), diethylstilbestrol (DES) is a nonsteroidal substance that was prescribed from the late 1940s to the early 1970s to pregnant women to prevent abortion, preeclampsia, and other complications of pregnancy. Male and female offspring exposed in utero to DES may develop multiple and neoplastic lesions of the reproductive tract, along with other changes, during development (10). Here we show that exposing fish oocytes to DES at a dose within a range similar to that used in experimental exposure to 17,20␤-DHP induces oocyte maturation. Estradiol-17␤ has been reported to be ineffective in inducing fish oocyte maturation (11, 12) and even inhibitory in several teleost species (13-15). Thus, the stimulatory effect of DES to induce fish oocyte maturation observed in this study has not been published previously. This report shows that EEDC can potentially induce oocyte maturation like an endogenous MIH, 17,20␤-DHP. Materials and MethodsMaterials. Goldfish were purchased from a local supplier and maintained at 15°C until used. Zebrafish were maintained at 28.5°C on a 14-h light͞10-h dark cycle (16). 17,20␤-DHP, DES, DES dimethyl ether (DM-DES), DES dipropionate (DP-DES), and 17␤-estradiol were purchased from Sigma. Dimethylstilbestrol (DMS) was a generous gift from J. Katzenellenbogen (University of Illinois, Urbana). 17␣-Estradiol, ethynylestradiol, butyl benzyl phthalate, di(2-ethylhexyl)-phthalate, and pentachlorophenol were obtained from Wako Pure Chemical (Osaka). Other chemicals were purchased as follows: hexestrol (HEX; ICN); trans,trans-dienestrol(␣-dienestrol) (DIES; U.S. Pharmacopeia, Rockville, MD); resveratorol (Calbiochem); DDTs (AccuStandard, New Haven, ...

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“…These receptors have considerable overlap in their inducer profiles and can interchangeably bind to their respective response elements even across species boundaries (7). Interestingly, CAR, PXR and CXR belong to the family of orphan nuclear receptors comprising also receptors involved in cholesterol homeostasis, namely the oxysterol receptor LXR (liver X receptor) and the bile acid receptor (BAR, alternatively also designated FXR) (8). Moreover, all these receptors form heterodimers with the retinoid X receptor (RXR) for binding to their recognition sequences.…”

Section: Introductionmentioning

confidence: 99%

A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

Ourlin

Handschin

Kaufmann

et al. 2002

Biochemical and Biophysical Research Communications

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Squalestatin1 (SQ1), a potent inhibitor of squalene synthase produced a dose-dependent induction of cytochromes P450 CYP2H1 and CYP3A37 mRNAs in chicken hepatoma cells. The effect of SQ1 was completely reversed by 25-hydroxycholesterol. Bile acids elicited an induction of CYP3A37 and CYP2H1 mRNA. Bile acids also reduced the phenobarbital induction of CYP2H1 but not of CYP3A37 mRNA. The effects of SQ1 and its reversal by 25-hydroxycholesterol and the effects of bile acids were reproduced in reporter gene assays with a phenobarbital-responsive enhancer unit of CYP2H1. These data suggest that an endogenous molecule related to cholesterol homeostasis regulates induction of drug-inducible CYPs.

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Orphan Nuclear Receptors: Shifting Endocrinology into Reverse

Cited by 466 publications

References 58 publications

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

Diethylstilbestrol induces fish oocyte maturation

A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

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