Nuclear Hormone Receptors, Metabolism, and Aging: What Goes Around Comes Around

Pardee, Keith; Reinking, Jeff; Krause, Henry M.

doi:10.1126/sageke.2004.47.re8

Cited by 23 publications

(6 citation statements)

References 106 publications

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“…It is also a required component of the cytochrome P450s that produce and break down most lipids, including those that serve as the ligands of most NRs [23,42,43,48,75–77]. More recently, heme has been shown to oscillate during the circadian cycle, to influence the circadian cycle, and to be a component of the circadian clock proteins Period 2 (mammalian PER 2 [mPER2]), NPAS2, and now the REV-ERBs [23,42,43,76,78]. Given that heme is so central to respiration and other central metabolic processes, and that its abundance appears to oscillate over time, we suggest that heme serves as a fundamental measure of the diurnal metabolic state and as such provides feedback through the REV-ERBs, and other clock proteins, to entrain the molecular clock.…”

Section: Discussionmentioning

confidence: 99%

The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ

et al. 2009

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Heme is a ligand for the human nuclear receptors (NR) REV-ERBα and REV-ERBβ, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV-ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ligand-binding domain (LBD). A 1.9 Å crystal structure of the REV-ERBβ LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-binding pocket, where the heme iron is coordinately bound by histidine 568 and cysteine 384. Under reducing conditions, spectroscopic studies of the heme-REV-ERBβ complex reveal that the Fe(II) form of the LBD transitions between penta-coordinated and hexa-coordinated structural states, neither of which possess the Cys384 bond observed in the oxidized state. In addition, the Fe(II) LBD is also able to bind either NO or CO, revealing a total of at least six structural states of the protein. The binding of known co-repressors is shown to be highly dependent upon these various liganded states. REV-ERBs are thus highly dynamic receptors that are responsive not only to heme, but also to redox and gas. Taken together, these findings suggest new mechanisms for the systemic coordination of molecular clocks and metabolism. They also raise the possibility for gas-based therapies for the many disorders associated with REV-ERB biological functions.

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Section: Discussionmentioning

confidence: 99%

The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ

et al. 2009

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“…NRs feature in most fundamental biological processes, functioning as key control points in diverse signaling and metabolic pathways, including electrolyte homeostasis (reviewed by DeLuca, 2004;Pearce, 2001), lipid metabolism and homeostasis (reviewed by Chawla et al, 2001), sex determination (reviewed by Iyer and McCabe, 2004), circadian rhythm and aging (reviewed in Pardee et al, 2004). NRs also play a central role in sensing xenobiotic compounds and coordinating an appropriate detoxification response (Willson and Kliewer, 2002).…”

Section: Introductionmentioning

confidence: 99%

Dynamic regulation ofDrosophilanuclear receptor activity in vivo

et al. 2006

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Nuclear receptors are a large family of transcription factors that play major roles in development, metamorphosis, metabolism and disease. To determine how, where and when nuclear receptors are regulated by small chemical ligands and/or protein partners, we have used a 'ligand sensor' system to visualize spatial activity patterns for each of the 18 Drosophila nuclear receptors in live developing animals. Transgenic lines were established that express the ligand binding domain of each nuclear receptor fused to the DNA-binding domain of yeast GAL4. When combined with a GAL4-responsive reporter gene, the fusion proteins show tissue-and stage-specific patterns of activation. We show that these responses accurately reflect the presence of endogenous and exogenously added hormone, and that they can be modulated by nuclear receptor partner proteins. The amnioserosa, yolk, midgut and fat body, which play major roles in lipid storage, metabolism and developmental timing, were identified as frequent sites of nuclear receptor activity. We also see dynamic changes in activation that are indicative of sweeping changes in ligand and/or co-factor production. The screening of a small compound library using this system identified the angular psoralen angelicin and the insect growth regulator fenoxycarb as activators of the Ultraspiracle (USP) ligand-binding domain. These results demonstrate the utility of this system for the functional dissection of nuclear receptor pathways and for the development of new receptor agonists and antagonists that can be used to modulate metabolism and disease and to develop more effective means of insect control.

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“…In previous work, we showed that ecdysone-induced protein 75 (E75, also known as Eip75B; NR1D3) (Tweedie et al 2009) contains heme constitutively bound to its ligand-binding domain (LBD), and that amino acids coordinately bound to the heme iron can be displaced in vitro by changes in redox state or the presence of nitric oxide (NO) gas (Pardee et al 2004;Reinking et al 2005;Marvin et al 2009). In turn, these structural changes negate the ability of E75 to repress transcription and to reverse the positive transcriptional activity of its heterodimer partner, Drosophila hormone receptor 3 (DHR3; also known as DHR46, NR1F4) (Tweedie et al 2009).…”

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Nitric oxide coordinates metabolism, growth, and development via the nuclear receptor E75

Cáceres¹,

Necakov²,

Schwartz³

et al. 2011

Genes Dev.

124

173

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Nitric oxide gas acts as a short-range signaling molecule in a vast array of important physiological processes, many of which include major changes in gene expression. How these genomic responses are induced, however, is poorly understood. Here, using genetic and chemical manipulations, we show that nitric oxide is produced in the Drosophila prothoracic gland, where it acts via the nuclear receptor ecdysone-induced protein 75 (E75), reversing its ability to interfere with its heterodimer partner, Drosophila hormone receptor 3 (DHR3). Manipulation of these interactions leads to gross alterations in feeding behavior, fat deposition, and developmental timing. These neuroendocrine interactions and consequences appear to be conserved in vertebrates.[Keywords: E75; DHR3; nitric oxide; Drosophila; metamorphosis; ecdysone; metabolism] Supplemental material is available for this article. In previous work, we showed that ecdysone-induced protein 75 (E75, also known as Eip75B; NR1D3) (Tweedie et al. 2009) contains heme constitutively bound to its ligand-binding domain (LBD), and that amino acids coordinately bound to the heme iron can be displaced in vitro by changes in redox state or the presence of nitric oxide (NO) gas (Pardee et al. 2004;Reinking et al. 2005;Marvin et al. 2009). In turn, these structural changes negate the ability of E75 to repress transcription and to reverse the positive transcriptional activity of its heterodimer partner, Drosophila hormone receptor 3 (DHR3; also known as DHR46, NR1F4) (Tweedie et al. 2009). Here, we look to see whether these interactions are relevant in vivo and, if so, what their roles are.One of the best-characterized roles of E75 and DHR3 in vivo is within the nuclear receptor (NR) transcriptional hierarchy that controls, and responds to, the production of the metamorphosis-inducing hormone ecdysone (diagrammed in Supplemental Fig. 1A). Upon binding ecdysone, the ecdysone receptor (EcR) acts as a heterodimer with a second NR, ultraspiracle (USP), to activate transcription of DHR3 and the E75 isoform E75A (Koelle et al. 1991;Lam et al. 1997Lam et al. , 1999White et al. 1997;Bialecki et al. 2002). DHR3 then promotes its own continued expression as well as that of the E75 splice variant E75B and the downstream NR gene bFtz-F1. bFTZ-F1, in turn, activates the expression of ecdysone synthetic enzyme genes (Lavorgna et al. 1993;Woodard et al. 1994;Broadus et al. 1999), resulting in another round of ecdysone production. The major site of larval ecdysone production is the prothoracic gland (PG) (diagrammed in Supplemental Fig. 1B). The PG is also a major site of NO synthase (Nos) expression (Wildemann and Bicker 1999). Hence, we looked to see whether E75 and NO are present and interactive in this tissue, with the hypothesis that activation of bFtz-F1 transcription by DHR3 requires inactivation of E75 isoforms by NO. As predicted, all of the above-listed genes are expressed in the PG toward the end of third instar development, and disruption of their expression or activity leads to molec...

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Nuclear Hormone Receptors, Metabolism, and Aging: What Goes Around Comes Around

Cited by 23 publications

References 106 publications

The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ

The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ

Dynamic regulation ofDrosophilanuclear receptor activity in vivo

Nitric oxide coordinates metabolism, growth, and development via the nuclear receptor E75

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