Ecdysteroid Receptors and their Applications in Agriculture and Medicine

University of Kentucky, Lexington, Kentucky, United States
Vitamins & Hormones (Impact Factor: 2.04). 02/2005; 73:59-100. DOI: 10.1016/S0083-6729(05)73003-X
Source: PubMed


Ecdysteroids (Ec) are signaling molecules widespread in the animal as well as in the plant kingdom (Lafont and Wilson, 1992). However, they do not occur naturally in vertebrates, a feature that makes them suitable as ligands in medical gene switch applications due to the reduced likelihood of pleiotropic effects. Ecdysteroids fulfill diverse tasks because they serve as hormones, pheromones, or insect deterrents (Nijhout, 1994). Their most frequent and prominent role, however, is their function as "molting hormones," thereby controlling not only insect and arthropod development but also reproduction and other physiological processes (Spindler, 1997). The action of Ec on target cells, as is the case with steroids in general, may be divided into fast and ephemeral (Tomaschko, 1999), as well as slow and systemic, effects. As will be discussed in the Section II.F., the two modes of Ec action may eventually converge, giving rise to the integral cellular response. Fast Ec effects are generally traced back to a not yet well-defined target on the cell membrane. On the other hand, the systemic effects involve an intracellular receptor, namely the ecdysteroid receptor (EcR) (Koelle et al., 1991). The EcR is a member of the nuclear receptor superfamily (Mangelsdorf and Evans, 1995; Mangelsdorf et al., 1995) and exhibits the typical modular structure composed of the N-terminal A/B domain, the DNA-binding C domain, the hinge (D) region, the ligand-binding E domain, and the C-terminal F domain. The ligand-binding domain is multifunctional and includes ligand-dependent dimerization and transactivation functions, while ligand-independent transactivation and dimerization functions are found in the terminal domains and in the region spanning the DNA binding domain and the N-terminal region of the hinge, respectively. The EcR heterodimerizes with other members of the nuclear receptor superfamily (Henrich, 2004), noticeably with the ultraspiracle protein (USP), which is an orthologue of the vertebrate retinoic acid X receptor (RXR) (Thomas et al., 1993; Yao et al., 1992, 1993). The EcR/USP heterodimers bind to the Ec response elements (EcRE) present in the promoter regions of Ec response genes and regulate their transcription. Most of the nuclear hormone receptors, including EcR, function as ligand-controlled transcription factors, a characteristic that renders these receptors or their key regions (i.e., the ligand- and DNA-binding domains) especially suitable as constituents of gene switches. Several nuclear receptors, including glucocorticoid receptor (GR), progesterone receptor (PR), estrogen receptor (ER), and EcR, are being used to develop gene switches for applications in medicine and agriculture. Since the EcR and its ligands are not found in vertebrates, they are attractive targets for the development of gene switches to be used in humans. This chapter is divided into Section I, which summarizes the present knowledge of the EcR's structure and function with special emphasis on those aspects that are relevant for gene switch applications, and Section II, which describes gene switch technology with a focus on EcR-based gene switches. For a comprehensive and comparative overview on EcR's role within the gene control network and during development and evolution, the reader is referred to Henrich (2004).

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    • "Nuclear receptors and other factors involved in ecdysteroid signaling pathways from D. melanogaster are valuable models for studying the mechanism of transcription modulation in vertebrates [13]. Mosquitoes, on the other hand, are the primary vectors of many devastating human diseases such as malaria and dengue, because they require blood as a nutrient source to promote egg development [14] [15]. "
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    ABSTRACT: The mosquito Aedes aegypti is the principal vector of dengue, one of the most devastating arthropod-borne viral infections in humans. The hypervariable in a sequence and length of the isoform-specific A/B region, called the N-terminal domain (NTD), is poorly evolutionarily conserved within the Ultraspiracle (Usp) family. The Usp protein together with ecdysteroid receptor (EcR) forms a heterodimeric complex. Up until now, there has been little data on the molecular properties of the isolated Usp NTD. Here, we describe the biochemical and biophysical properties of the recombinant NTD of the Usp isoform B (aaUsp-NTD) from Aedes aegypti. The results, along with in silico bioinformatic examinations, indicate that aaUsp-NTD exhibits properties of an intrinsically disordered protein (IDP). We also present the first experimental evidence describing the dimerization propensity of the isolated NTD of Usp. These characteristics also appear for other members of the Usp family in different species, for example, in the Usp-NTD from D. melanogaster and B. mori. However, aaUsp-NTD exhibits the strongest homodimerization potential. We postulate that the unique dimerization of the NTD might be important for Usp functioning by providing an additional platform for interactions, in addition to the nuclear receptor superfamily dimerization via DNA-binding domains and ligand-binding domains that has already been extensively documented. Furthermore, the unique NTD-NTD interaction that was observed might contribute new insight into the dimerization propensities of nuclear receptors.
    Full-text · Article · Apr 2014 · Biochimica et Biophysica Acta
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    • "However, the other 20 NRs, which also harbor important functions, have not been exploited for development of insecticides. Several NRs including EcR, PR, GR and ER are being used for development of gene switches for use in medicine and agriculture (Palli et al, 2005). Knowledge in function of NRs in insects will aid in development of both insecticides and gene switches. "
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    ABSTRACT: Nineteen canonical and two Knirps-like family nuclear receptors (NRs) were identified in the genome of Tribolium castaneum. The current study was conducted to determine the function of these NRs in regulation of female reproduction and embryogenesis. RNA interference (RNAi)-aided knock-down in the expression of genes coding for 21 NRs showed that seven NRs E75, hormone receptor 3 (HR3), ecdysone receptor (EcR), ultraspiracle (USP), seven-up (SVP), FTZ transcription factor 1 (FTZ-F1) and hormone receptor 4 (HR4) are required for successful vitellogenesis and oogenesis. Knocking down the expression of genes coding for these seven NRs affected egg production by reducing the levels of vitellogenin mRNAs as well as by affecting the oocyte maturation. Expression of seven additional NRs hormone receptor 96 (HR96), hormone receptor 51 (HR51), hormone receptor 38 (HR38), hormone receptor 39 (HR39), Tailless (Tll), Dissatisfaction (Dsf) and Knirps-like is required for successful embryogenesis. The knock-down in the expression of genes coding for three other NRs (E78, hepatocyte nuclear factor 4, HNF4 and Eagle) partially blocked embryogenesis. This study showed that at least 17 out of the 21 NRs identified in T. castaneum play key roles in female reproduction and embryogenesis.
    Full-text · Article · Apr 2010 · Journal of insect physiology
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    • "In the absence of 20E, EcR-USP associates with co-repressors, binds to the 20E-response elements, and represses transcription of the 20E primary response genes. After binding 20E to form the 20E-EcR- USP complex, this ligand-receptor complex recruits co-activators and then induces the 20E-triggered transcriptional cascade, which includes the 20E primary and secondary response genes (Gilbert et al., 2000; Riddiford et al., 2003; Palli et al., 2005). "
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    ABSTRACT: Juvenile hormone (JH) regulates many developmental and physiological events in insects, but its molecular mechanism remains conjectural. Here we report that genetic ablation of the corpus allatum cells of the Drosophila ring gland (the JH source) resulted in JH deficiency, pupal lethality and precocious and enhanced programmed cell death (PCD) of the larval fat body. In the fat body of the JH-deficient animals, Dronc and Drice, two caspase genes that are crucial for PCD induced by the molting hormone 20-hydroxyecdysone (20E), were significantly upregulated. These results demonstrated that JH antagonizes 20E-induced PCD by restricting the mRNA levels of Dronc and Drice. The antagonizing effect of JH on 20E-induced PCD in the fat body was further confirmed in the JH-deficient animals by 20E treatment and RNA interference of the 20E receptor EcR. Moreover, MET and GCE, the bHLH-PAS transcription factors involved in JH action, were shown to induce PCD by upregulating Dronc and Drice. In the Met- and gce-deficient animals, Dronc and Drice were downregulated, whereas in the Met-overexpression fat body, Dronc and Drice were significantly upregulated leading to precocious and enhanced PCD, and this upregulation could be suppressed by application of the JH agonist methoprene. For the first time, we demonstrate that JH counteracts MET and GCE to prevent caspase-dependent PCD in controlling fat body remodeling and larval-pupal metamorphosis in Drosophila.
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