The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila

King-Jones, Kirst; Horner, Michael A.; Lam, Geanette; Thummel, Carl S.

doi:10.1016/j.cmet.2006.06.006

Cited by 184 publications

(234 citation statements)

References 62 publications

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“…Consistent with this, we found that DHR96 is expressed in the region of the larval midgut, where npc1b exerts its functions ( Fig. 4A; King-Jones et al 2006;Voght et al 2007). This overlap in DHR96 and npc1b expression also appears to be functionally significant because specific expression of wild-type DHR96 in the midgut of DHR96 mutants is sufficient to restore appropriate npc1b transcriptional repression in response to cholesterol (Fig.…”

Section: Dhr96 Mutants Accumulate Cholesterolsupporting

confidence: 71%

“…Thus, it is likely that the DHR96 mutants suffer from additional metabolic defects beyond their inability to properly regulate npc1b transcription. This conclusion is supported by the widespread effects of the DHR96 mutation on the expression of genes involved in lipid metabolism and midgut physiology, as well as the expression of DHR96 in tissues outside the midgut (King-Jones et al 2006). Further studies of DHR96 mutants should help to uncover its other key metabolic activities.…”

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 60%

“…All studies were performed using Canton-S (CanS) wild-type flies and DHR96 1 -null mutants that had been crossed to CanS for nine generations (King-Jones et al 2006). The following stocks were used in this study: npc1a 1 (from M. Scott), npc1b 1 and NPC1b-GAL4 (both from L. Pallanck), CG-Gal4 (Hennig et al 2006), and Mex-Gal4 (Phillips and Thomas 2006).…”

Section: Drosophila Stocksmentioning

confidence: 99%

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The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

Horner¹,

Pardee²,

et al. 2009

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Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis. Cholesterol is an essential component of cell membranes that influences the permeability and fluidity of the lipid bilayer. Cholesterol also acts as a precursor for steroid hormone biosynthesis and contributes to cell-cell signaling pathways. These critical cellular functions are supported by regulatory mechanisms that maintain normal cholesterol levels and prevent hypercholesterolemia, which is a major risk factor for cardiovascular disease in humans. Cholesterol homeostasis in vertebrates is achieved primarily through de novo synthesis and dietary uptake (Ikonen 2008). Although extensive studies have defined a central role for the sterol regulatory elementbinding protein (SREBP) family of transcription factors in controlling cholesterol synthesis (Brown and Goldstein 1997), the mechanisms that regulate dietary cholesterol absorption remain more poorly understood. One central component of this pathway is the Niemann-Pick C1-like 1 gene NPC1L1, which encodes a plasma membrane protein that mediates the uptake of dietary cholesterol by the intestine (Wang 2007;Ge et al. 2008). Mouse mutants for NPC1L1 display significantly reduced levels of cholesterol absorption and are insensitive to treatment with the anti-hypercholesterolemia drug ezetimibe, which acts as a specific NPC1L1 inhibitor (Davis et al. 2008). Another major regulator of cholesterol homeostasis is the liver X receptor a (LXRa) nuclear receptor, which binds cholesterol metabolites and regulates the transcription of genes that control cholesterol transport and metabolism, including NPC1L1 (Duval et al. 2006;Kalaany and Mangelsdorf 2006;Valasek et al. 2007).We used the fruit fly, Drosophila, as a model system to study the regulation of cholesterol homeostasis. Unlike vertebrates, insects are cholesterol auxotrophs that are unable to synthesize this essential compound (Va'nt Hoog 1936). Little is known, however, about the mechanisms that regulate the uptake of dietary cholesterol in Drosophila. A recent study showed that the fly ortholog of NPC1L1, npc1b, is expressed specifically in the midgut and is essential for dietary cholesterol absorption (Voght et al. 2007). Other NPC disease gene homologs in Drosophila also contribute to cholesterol homeostasis. The Drosophila ortholog of vert...

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Section: Dhr96 Mutants Accumulate Cholesterolsupporting

confidence: 71%

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 60%

Section: Drosophila Stocksmentioning

confidence: 99%

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The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

Horner¹,

Pardee²,

et al. 2009

Self Cite

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“…In addition, we tested media containing another compound, phenobarbital (PB), to examine whether responses were specific to caffeine or of a more general nature. Like caffeine, PB is a potent inducer of detoxification responses in the fly, 37 but its biological activity is based on a different mechanism, because PB acts by stimulating GABA receptors. We then scored for obvious phenotypes (morphological changes and lethality) on either media type.…”

Section: Resultsmentioning

confidence: 99%

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. Throughout their lives, organisms are exposed to a wide range of harmful substances. These compounds, often referred to as xenobiotics, may enter the body through direct contact, inhalation or ingestion, and can originate from many sources including pharmaceuticals, pesticides, plant toxins and pollutants. The ubiquitous and varied nature of xenobiotic pressure is reflected in the complexity of conserved cellular defense mechanisms that respond to these chemical compounds, and metazoans have thus developed a range of pathways that activate survival responses or trigger programmed cell death to eliminate damaged cells. 1 Xenobiotic pathways control the expression and activation of heat shock proteins, oxidative stress components, DNA repair enzymes, hypoxia response factors and several groups of xenobiotic-metabolizing enzymes. In eukaryotes, environmental challenges that activate stress response programs are relayed through a complex signaling cascade. Some stress pathways respond to very specific compounds, whereas others, such as those depending on Mitogen-activated protein kinases, propagate stress signals from a broad spectrum of stimuli. 1-3 Despite the importance that stress response pathways play in pharmacology and toxicology, we still have a relatively poor understanding of the complex networks that launch these cellular defense systems.We performed a quantitative cell-culture RNA interference (RNAi) assay of Drosophila kinases and phosphatases to identify key regulators of stress response pathways that reac...

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“…Approaches, such as sex-specific expression of P450s, induction capacity of P450s by various exogenous compounds, and transcriptional profiling have been useful in characterizing P450 functions (39)(40)(41)(42). In an effort to distinguish P450s with essential endogenous functions from those involved in detoxification, we characterized expression patterns of D. melanogaster P450s by in situ hybridization and performed a P450 RNA interference (RNAi) knockdown screen.…”

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confidence: 99%

Characterization of Drosophila melanogaster cytochrome P450 genes

Chung

Sztal

Pasricha

et al. 2009

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

259

235

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Cytochrome P450s form a large and diverse family of hemecontaining proteins capable of carrying out many different enzymatic reactions. In both mammals and plants, some P450s are known to carry out reactions essential for processes such as hormone synthesis, while other P450s are involved in the detoxification of environmental compounds. In general, functions of insect P450s are less well understood. We characterized Drosophila melanogaster P450 expression patterns in embryos and 2 stages of third instar larvae. We identified numerous P450s expressed in the fat body, Malpighian (renal) tubules, and in distinct regions of the midgut, consistent with hypothesized roles in detoxification processes, and other P450s expressed in organs such as the gonads, corpora allata, oenocytes, hindgut, and brain. Combining expression pattern data with an RNA interference lethality screen of individual P450s, we identify candidate P450s essential for developmental processes and distinguish them from P450s with potential functions in detoxification.detoxification genes ͉ in situ hybridization ͉ insecticide resistance ͉ multigene family ͉ RNAi

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The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila

Cited by 184 publications

References 62 publications

The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

The Hippo pathway promotes cell survival in response to chemical stress

Characterization of Drosophila melanogaster cytochrome P450 genes

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