Showing papers on "Aryl hydrocarbon receptor nuclear translocator published in 2006"
TL;DR: The hypothesis is emerging that the diverse tissue-specific, TCDD-mediated toxicities are due to sustained and inappropriate AhR activation leading to deregulated physiologic functions, and recent observations in the context of some TCDDs toxic responses are discussed.
334 citations
TL;DR: It is demonstrated that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo and fenofibrate induces calendar rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo.
Abstract: Recent evidence has emerged that peroxisome proliferator-activated receptor α (PPARα), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPARα influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARα plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARα on a potential PPARα response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARα gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an ...
309 citations
TL;DR: It is found that curcumin inhibits Hif-1 activity and that this in turn down-regulates genes targeted by HIF-1, and the results suggest that the anticancer activity ofCurcumin is attributable to H IF-1 inactivation by ARNT degradation.
Abstract: Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and aryl hydrocarbon receptor nuclear translocator (ARNT), plays a key role in cell survival and angiogenesis in hypoxic tumors, and many efforts have been made to develop anticancer agents that target HIF-1alpha. However, although ARNT is also required for HIF-1 activity, ARNT has been disregarded as a therapeutic target. Curcumin is a commonly used spice and coloring agent with a variety of beneficial biological effects, which include tumor inhibition. In the present study, we tested the possibility that curcumin inhibits tumor growth by targeting HIF-1. The effects of curcumin on HIF-1 activity and expression were examined in cancer cell lines and in xenografted tumors. We found that curcumin inhibits HIF-1 activity and that this in turn down-regulates genes targeted by HIF-1. Moreover, of the two HIF-1 subunits, only ARNT was found to be destabilized by curcumin in several cancer cell types, and furthermore, ARNT expression rescued HIF-1 repression by curcumin. We also found that curcumin stimulated the proteasomal degradation of ARNT via oxidation and ubiquitination processes. In mice bearing Hep3B hepatoma, curcumin retarded tumor growth and suppressed ARNT, erythropoietin, and vascular endothelial growth factor in tumors. These results suggest that the anticancer activity of curcumin is attributable to HIF-1 inactivation by ARNT degradation.
208 citations
TL;DR: These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity, and the growing use of molecular and genomic tools for research on zebrafish have led to advances in understanding of the mechanism of TCDd developmental toxicity at the molecular level.
Abstract: Zebrafish (Danio rerio) have advantages over mammals as an animal model for investigating developmental toxicity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a persistent global contaminant, is the most comprehensively studied developmental toxicant in zebrafish. The hallmark responses of TCDD developmental toxicity manifested in zebrafish larvae include edema, anemia, hemorrhage, and ischemia associated with arrested growth and development. Heart and vasculature development and function are severely impaired, and jaw malformations occur secondary to inhibited chondrogenesis. The swim bladder fails to inflate, and the switch from embryonic to adult erythropoiesis is blocked. This profile of developmental toxicity responses, commonly referred to as "blue sac syndrome" because the edematous yolk sac appears blue, is observed in the larval form of all freshwater fish species exposed to TCDD at the embryonic stage of development. Components of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AHR/ARNT) signaling pathway in zebrafish have been identified and functionally characterized. Their role in mediating TCDD toxicity has been determined using morpholinos to specifically knockdown the translation of zfAHR1, zfAHR2, zfARNT1, and zfARNT2 mRNAs, respectively, and a line of zfARNT2 null mutant zebrafish has provided further insight. These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity. In addition, the growing use of molecular and genomic tools for research on zebrafish have led to advances in our understanding of the mechanism of TCDD developmental toxicity at the molecular level, including the recent finding that toxicity is not mediated by increased cytochrome P4501A (zfCYP1A) expression.
168 citations
TL;DR: This commentary appraises the current literature on factors that regulate A HR levels/activity and attempts to identify fruitful strategies towards discovery of key pathways by which AHR levels are modulated in response to endogenous signals and in responseto xenobiotic chemicals.
156 citations
TL;DR: The results suggest that HIF-1 mediates hypoxia-induced IGFBP-1 gene expression in early development by selectively interacting with the −1090/−1086 HRE and its adjacent HAS.
Abstract: Hypoxia triggers the transcription of regulatory genes that promote O2 delivery and anaerobic metabolism, suppress major energy-requiring processes, and inhibit growth and development in animals ranging from invertebrates to mammals (14, 15, 40). Hypoxia also influences several human pathological processes, such as tumorigenesis and intrauterine growth restriction (IUGR). The majority of these transcriptional responses to hypoxia are mediated by the hypoxia-inducible factor 1 (HIF-1) complex. HIF-1 is a heterodimeric complex composed of HIF-1α and HIF-1β (44, 45). HIF-1β, also known as aryl hydrocarbon receptor nuclear translocator, is constitutively expressed and insensitive to O2 availability. When oxygen levels are high, HIF-1α is bound to the von Hippel-Lindau tumor suppressor (pVHL) and targeted for ubiquitination and proteosomal degradation (30, 34). Hypoxic conditions inhibit this degradation, which allows HIF-1α to accumulate in the cell (16, 18, 27). HIF-1α is then translocated to the nucleus, dimerizes with HIF-1β, binds to DNA, and activates target gene expression (3). Hypoxia response elements (HREs) are cis-regulatory DNA sequences that specifically bind to HIF-1 and are required for transcriptional induction upon hypoxia exposure.
Insulin-like growth factor binding protein 1 (IGFBP-1) is a hypoxia-inducible gene. Earlier studies have shown that circulating levels of IGFBP-1 are elevated in IUGR fetuses (7, 12, 42, 43). In vitro studies using cultured human cells and in vivo studies using rodent and fish models suggest that IGFBP-1 gene expression is elevated under hypoxic conditions (13, 29, 31, 35, 41). Since IGFBP-1 binds IGFs and inhibits IGF action on cell growth in vitro (4, 9) and because IGFBP-1 overexpression reduced birth weights in mice (5, 11, 36), it was postulated that elevated IGFBP-1 plays a major role in hypoxia-induced IUGR by binding IGFs and inhibiting their growth-promoting activities (41). Using the transparent and free-living zebra fish embryo as a model system, we have recently shown that (i) hypoxia strongly up-regulates IGFBP-1 expression and delays growth and developmental rate in zebra fish embryos; (ii) IGFBP-1 knockdown partially abrogates these hypoxic effects, whereas IGFBP-1 overexpression decreases growth and developmental rates under normoxia; and (iii) reintroduction of IGFBP-1 to the knocked down embryos restores the hypoxic effects (19). These findings provide strong evidence arguing that up-regulation of IGFBP-1 by hypoxia plays a key role in coordinating embryonic growth rate and developmental timing in response to environmental oxygen availability. Although there is in vitro evidence that overexpression of HIF-1α in cultured human hepatoma (HepG2) cells increases human IGFBP-1 promoter activity (41), how hypoxia triggers IGFBP-1 gene expression in vivo is not clear, and the cis-regulatory elements responsible for hypoxia-induced IGFBP-1 transcription in vivo are not well defined.
The objectives of this study are (i) to determine when the HIF-1 pathway becomes operational in early development and whether it plays a role in mediating hypoxia-induced IGFBP-1 gene expression in zebra fish embryos and (ii) to identify the key cis-regulatory element(s) responsible for hypoxia-induced IGFBP-1 transcription in vivo. Our results indicate that the HIF-1 pathway is established and operational in the earliest stages of vertebrate development and that it plays a major role in mediating hypoxia-induced IGFBP-1 gene expression in zebra fish embryos in vivo. Intriguingly, although the zebra fish IGFBP-1 promoter contains 13 consensus HREs, only one of these HREs is required for the hypoxia/HIF-1 regulation of IGFBP-1 gene expression in vivo. We show that a HIF-1 ancillary sequence (HAS) adjacent to the functional HRE is critical for its hypoxia/HIF-1 responsiveness.
152 citations
TL;DR: It is reported that blocking zfAHR2 and zfARNT1 expression provided protection against the TCDD-mediated alteration in heart morphology, reduced cardiac myocyte number, decreased cardiac output and ventricular standstill in zebrafish larvae, while the zfarnt2 andZfcyp1a morpholinos did not block the T CDD-induced cardiac toxicity.
120 citations
TL;DR: It is proposed that exposure to environmental chemicals that activate the aryl hydrocarbon receptor pathway contribute to melanoma progression, specifically through stimulation of the expression and activity of the matrix metalloproteinases (MMPs).
103 citations
TL;DR: Current knowledge and existing concepts that help to understand how cytokines and hormones affect protein accumulation of HIF-1alpha are summarized and potential implications of activating Hif-1 under normoxia are discussed.
Abstract: Hypoxia inducible factor-1 (HIF-1) is a central component of the oxygen sensing system that coordinates cellular responses to conditions of decreased oxygen availability. The hypoxia inducible transcription factor HIF-1 is a heterodimer composed of the helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) proteins HIF-1alpha and the aryl hydrocarbon nuclear translocator (ARNT) also known as HIF-1beta. Transactivation of HIF-1 transmits a hypoxic signal into patho-physiological responses such as angiogenesis, erythropoiesis, vasomotor control, an altered energy metabolism, as well as cell survival decisions by regulating a staidly growing number of target genes. Among recent advances are the discoveries that cytokines and growth factors make use of the 'hypoxic signaling system' under normoxia. Here we summarize current knowledge and existing concepts that help to understand how cytokines and hormones affect protein accumulation of HIF-1alpha and discuss potential implications of activating HIF-1 under normoxia. Considering the fundamental role of cytokines during inflammation may predict a role of HIF-1alpha in coordinating cellular responses to pathogens and point to the connection of cancer and inflammation. Moreover, we will address potential feed-back mechanisms showing an impact of HIF-1 on cytokine production. These considerations suggest an intimate signaling cross-talk between cytokines and the HIF-1 system.
91 citations
TL;DR: The antiestrogenic effect of TCDD demonstrated raises further concerns about the neuroendocrine effects of AhR ligands and provides data on the functionality of DREs predicted in zfcyp19 promoters.
84 citations
TL;DR: HIF-1?
Abstract: Hypoxia promotes metastatic potential of tumor cells by largely unknown mechanisms. Hypoxia inducible factor (HIF) is a heterodimeric transcription factor consisting of alpha and beta (ARNT) subunits and plays an important role in tumor microenvironment. CXCR4 is a cell surface receptor that has been shown to mediate the metastasis of various tumors. CXCR4 induction by hypoxia is dependent on both activation of HIF and transcript stabilization. To investigate the mechanisms involved in hypoxia-induced metastasis and hypoxia-mediated chemokine receptor CXCR4 expression, we used lentiviral vector mediated RNA interfering (RNAi) to knock down expression of HIF-1alpha or HIF-2alpha in two NSCLC cell lines to investigate HIF-dependent invasion, migration and adhesion. Here we show that: (1) hypoxia is an important factor in regulating CXCR4 mediated metastasis and the cells exhibited reducing invasion, adhesion and migration in response to CXCL12 after knocking down HIF. (2) HIF-1alpha and HIF-2alpha are essential for hypoxic cellular response to cancer invasion and adhesion through upregulation of CXCR4. HIF-1alpha and HIF-2alpha are playing important roles in tumor metastasis, which may offer for future intervention strategies. We also show that the lentivirus mediated RNAi technology is very effective on knocking down gene expression.
TL;DR: It is demonstrated that TCDD specifically blocks regenerative growth in larvae, and it is reported that zfAHR2 and zfARNT1 are the in vivo dimerization partners that are required for inhibition of regeneration by T CDD.
Abstract: There is considerable literature supporting the conclusion that inappropriate activation of the aryl hydrocarbon receptor (AHR) alters cellular signaling. We have established previously that fin regeneration is specifically inhibited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in adult zebrafish and have used this in vivo endpoint to evaluate interactions between AHR and growth-controlling pathways. Because there are experimental limitations in studying regeneration in adult animals, we have developed a larval model to evaluate the effect of AHR activation on tissue regeneration. Two-day-old zebrafish regenerate their amputated caudal fins within 3 days. Here, we demonstrate that TCDD specifically blocks regenerative growth in larvae. The AHR pathway in zebrafish is considerably more complex than in mammals, with at least three zebrafish AHR genes (zfAHR1a, zfAHR1b, and zfAHR2) and two ARNT genes (zfARNT1 and zfARNT2). Although it was presumed that the block in regeneration was mediated by AHR activation, it had not been experimentally demonstrated. Using antisense morpholinos and mutant fish lines, we report that zfAHR2 and zfARNT1 are the in vivo dimerization partners that are required for inhibition of regeneration by TCDD. Several pathways including fibroblast growth factor (FGF) signaling are essential for fin regeneration. Even though impaired FGF signaling and TCDD exposure both inhibit fin regeneration, their morphometric response is distinct, suggesting that the mechanisms of impairment are different. With the plethora of molecular and genetic techniques that can be applied to larval-stage embryos, this in vivo regeneration system can be further exploited to understand cross-talk between AHR and other signaling pathways.
TL;DR: It is shown that activation of the AhR by TCDD disrupts the circadian rhythms associated with murine hematopoietic precursors and Modest changes in the 24-h expression of mPer1 and mPer2 mRNA and increased AhR repressor mRNA after T CDD exposure suggest a direct effect on the molecular machinery responsible for these rhythms.
Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) agonist, has been identified as a potent immunohematopoietic toxicant with the ability to alter the number of Lin(-) Sca-1(+) cKit(+) (LSK) bone marrow cells, a population enriched for murine hematopoietic stem cells. The biology of these cells is governed by circadian rhythms and TCDD has been shown to disrupt circadian rhythms of other biological endpoints. We investigated the effect of TCDD on the circadian rhythms of hematopoietic precursors. Female C57BL/6 mice were treated with a single oral dose of 10 mug/kg TCDD. Five days later, bone marrow was harvested every 4 h for 24 h and stained for specific hematopoietic populations using fluorescently labeled antibodies. In addition, cells were placed into semisolid culture to measure different functionally defined populations. Activation of the AhR by TCDD elicited disruptions in the rhythms of LSK cell numbers and phenotypically defined myeloid and erythroid precursors. Simultaneous DNA and RNA staining revealed an abnormal in vivo rhythm of percentage of total number of LSK cells in G(0) phase of the cell cycle, suggesting disruption of stem cell quiescence. Finally, quantitative reverse transcription-polymerase chain reaction revealed that expression of AhR and Arnt mRNA within enriched hematopoietic precursors oscillates with a circadian period. Modest changes in the 24-h expression of mPer1 and mPer2 mRNA and increased AhR repressor mRNA after TCDD exposure suggest a direct effect on the molecular machinery responsible for these rhythms. Together, these data demonstrate that activation of the AhR by TCDD disrupts the circadian rhythms associated with murine hematopoietic precursors.
TL;DR: Results indicate that binding of the ligands to AhR up-regulates the mRNA transcription not only of CYP1A1 and NQO1, but also of AhR itself, which depends on the potency of xenobiotic metabolizing enzymes inducer.
TL;DR: Recent findings on the structure-function relationships of EcDOS are reviewed to clarify how the heme redox-dependent structural changes initiate intramolecular signal transduction.
Abstract: Recent studies have revealed a new class of heme enzymes, the heme-based sensors, which are able to turn on or off cellular signal transduction pathways in response to environmental changes. One of these enzymes is the heme-regulated phosphodiesterase from Escherichia coli (EcDOS). This protein is composed of an N-terminal heme-containing PAS domain and a C-terminal functional domain. PAS is an acronym formed from the names of the Drosophila period clock protein (PER), vertebrate aryl hydrocarbon receptor nuclear translocator (ARNT), and Drosophila single-minded protein (SIM). The heme cofactor in its PAS domain can act as a sensor of the cellular redox state that regulates the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase activity. The crystal structures of its heme-containing PAS domain have helped clarify how the heme redox-dependent structural changes initiate intramolecular signal transduction. Here, we review recent findings on the structure-function relationships of EcDOS.
TL;DR: Tissue distribution of AhRR in AhR deficient and wild type C57BL/6 mice is reported and simultaneous measurements of CYP1A1 and AhRR mRNA expression do not strongly support the view that the AhRR tissue pattern triggers the tissue specific responsiveness of AhR-regulated genes to B(a)P treatment.
Abstract: The Aryl hydrocarbon receptor repressor (AhRR) is a new member of bHLH-PAS proteins which is important in the regulation of cell growth and differentiation. The AhRR shares structural similarities with Aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT). The AhRR is thought to be involved in transcriptional control of AhR-regulated genes by sequestering ARNT. Most of the knowledge of regulation and function of the AhRR is from studies in cell lines. Here, we report the tissue distribution of AhRR in AhR deficient and wild type C57BL/6 mice. In addition, the inducibility of the AhRR and Cytochrome P450 (CYP) 1A1 in response to benzo(a)pyrene (B(a)P) (10 mg/kg bw i.p.) was investigated. The results show that the AhRR mRNA expression pattern in untreated C57BL/6 mice varies across tissues with high levels in hearts and brains. In other tissues, AhRR mRNA expression was low. In contrast to wild-type animals, the tissue levels in AhR-/- mice were about two to three orders of magnitude lower. Treatment of wild-type animals with B(a)P resulted in an induced AhRR expression in liver, spleen, lung and ovary. No significant induction of AhRR mRNA was found in brain and heart tissues, which have a constitutively high level of AhRR expression. Simultaneous measurements of CYP1A1 and AhRR mRNA expression do not strongly support the view that the AhRR tissue pattern triggers the tissue specific responsiveness of AhR-regulated genes to B(a)P treatment.
TL;DR: Clear functional differences are observed in the ability of Arnt and Arnt2 to induce xenobiotic response element-driven reporter and endogenous CYP1A1 gene expression and the induction of endogenous Glut-1 through binding with HIFα in response to hypoxia.
TL;DR: Results suggest that inhibitory AhR-ERalpha/Sp1 cross talk is due, in part, to enhanced association of AhR and ERalpha (also determined by fluorescence resonance energy transfer), which coordinately dissociates ER and Sp1 and decreases ERalpha-Sp1-mediated transactivation, whereas remaining associated with the CAD promoter.
Abstract: The trifunctional carbamoylphosphate synthetase/aspartate transcarbamyltransferase/dihydroorotase (CAD) gene is hormone responsive in MCF-7 and ZR-75 breast cancer cells, and this response is inhibited by the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Estrogen-dependent induction of CAD mRNA and reporter gene activity in cells transfected with constructs (pCAD) containing hormone-responsive GC-rich CAD promoter inserts involves estrogen receptor alpha (ERalpha)/Sp1 interactions with these proximal GC-rich motifs. TCDD also inhibits hormone-induced transactivation in MCF-7 and ZR-75 cells transfected with pCAD constructs. The mechanism of inhibitory AhR-ERalpha/Sp1 cross talk was further investigated by chromatin immunoprecipitation (ChIP), and the results show that ERalpha/Sp1 and the AhR are constitutively bound to the CAD gene promoter and only minor changes are observed after treatment with 17beta-estradiol, TCDD, or their combination. However, examination of interactions of these transcription factors by fluorescence resonance energy transfer shows that E2 enhances ERalpha-Sp1 interactions, whereas cotreatment with TCDD significantly decreases interaction of these proteins. These results suggest that inhibitory AhR-ERalpha/Sp1 cross talk is due, in part, to enhanced association of AhR and ERalpha (also determined by fluorescence resonance energy transfer), which coordinately dissociates ER and Sp1 and decreases ERalpha/Sp1-mediated transactivation, whereas remaining associated with the CAD promoter. This represents a novel interaction between two ligand activated receptors where one receptor inhibits activation of the second receptor.
TL;DR: It is concluded that the AHR-1:AHA-1 transcription complex regulates the expression of soluble guanylate cyclase genes and other unidentified genes that are essential for acute regulation of aggregation behavior.
TL;DR: The results show that the human AHR is degraded in a ligand dependent manner following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin for up to 16h, which indicates that ligand-dependent and independent degradation of the A HR is a conserved aspect of this signal transduction cascade from fish to human.
TL;DR: The findings suggest that BRCA1 may be physiologically important for mounting a normal response to xenobiotic insults and that it may function as a coactivator for ARNT activity.
TL;DR: Results indicate that expression of proteasome subunit PSMB5 is modulated by bifunctional enzyme inducers in a manner independent of the AhR/Arnt-XRE pathway but dependent upon the Nrf2-ARE pathway.
TL;DR: The TCDD-dependent activation of a subset of retinoid-dependent genes (tissue-transglutaminase, IGF binding protein-3, AhR) in MCF-7 breast cancer cells revealed the ability of AhR to elicit spurious activation of Retinoid receptors, expanding the scope of Ahr ligands influence beyond ER antagonism and specific Dioxin-responsive genes.
TL;DR: It is shown that Arnt is expressed in human and mouse skin in a developmentally dependent manner and functional defects in Arnt-null mouse epidermis underscore the crucial role of Arnt in the maintenance of epidermal homeostasis, especially during the perinatal transition to the ex utero environment.
Abstract: The molecular mechanisms of skin adaptation to the environmental stress are poorly understood. The aryl hydrocarbon receptor nuclear translocator (Arnt) lies at the intersection of several crucial adaptive pathways. Nevertheless, its role in adaptation of the skin to environmental stress has just begun to be unraveled. Here we show that Arnt is expressed in human and mouse skin in a developmentally dependent manner. Targeted K14-driven deletion of Arnt in the mouse epidermis resulted in early postnatal death, associated with a failure of epidermal barrier function. Gene expression profiling of Arnt-null mouse epidermis revealed upregulation of genes of the epidermal differentiation complex on mouse chromosome 3, including S100a genes (S100a8, S100a9, S100a10) and genes coding for small proline-rich proteins (Sprr1a, Sprr2i, Sprr2j, Sprrl1). HPTLC analysis showed significant accumulation of Cer[NS] and Cer[NH] ceramide species in Arnt-null epidermis, suggesting alterations in lipid metabolism. Continuous retention of corneosomes in Arnt-null epidermis that resulted in an abnormally dense corny layer and impaired desquamation was associated with upregulation of Slpi, an inhibitor of stratum corneum chymotryptic enzyme (SCCE) that plays a key role in corneosome degradation. The functional defects in Arnt-null mouse epidermis underscore the crucial role of Arnt in the maintenance of epidermal homeostasis, especially during the perinatal transition to the ex utero environment.
TL;DR: Sim2s as discussed by the authors is a splice variant of Sim2, which is missing the carboxyl Pro/Ala-rich repressive domain and is expressed at high levels in kidney and skeletal muscle.
TL;DR: The promise associated with the use of flavonoids, that inhibit both AHR signaling and the carcinogenic actions of AHR agonists, for chemopreventive purposes is illustrated.
Abstract: The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which upon activation by its agonists, translocates into the nucleus and forms a dimer with ARNT (aryl hydrocarbon nuclear translocator). The AHR/ARNT dimer regulates the expression of its target genes by binding to DNA recognition elements termed dioxin responsive elements (DREs). Many AHR agonists, like the polyaromatic hydrocarbons and polyhalogenated hydrocarbons are known human carcinogens. Human exposure to these compounds is common due to their presence in air pollution and cigarette smoke. Interestingly, many dietary constituents that have chemo preventative properties have been found to also act as antagonists of the AHR pathway. Thus, a chemopreventive approach that may be effective in decreasing the incidences of many human cancers may involve a dietary regimen that includes a number of these naturally occurring AHR antagonists. With this idea in mind, we have assayed the ability of 15 flavonoids to inhibit AHR activated reporter activity and selected kaempferol for further analysis. Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. Using an in vitro paradigm of events that are thought to occur during cigarette-smoke-induced lung cancer, we found that kaempferol also inhibited the ability of cigarette smoke condensate to induce growth of immortalized lung epithelial (BEAS-2B) cells in soft agar. Taken together, these results illustrate the promise associated with the use of flavonoids, that inhibit both AHR signaling and the carcinogenic actions of AHR agonists, for chemopreventive purposes.
TL;DR: In conclusion, endothelial Arnt plays a pivotal role in embryonic liver development and develops what was possibly an early stage of cirrhosis with consequences of limited oxygen availability and altered lipid metabolism.
TL;DR: It is demonstrated here that NcoA4, a nuclear receptor coactivator, interacts with and amplifies AhR action and was abolished by overexpression of androgen receptor, suggesting a potential competition of AhR and androgen receptors for Nco a4.
TL;DR: Thyrocytes are targets of TCDD and T CDD-like compounds and there is evidence for two independent most likely AhR-mediated molecular mechanisms, by which these compounds negatively interfere with thyroid function.
TL;DR: The results suggest that HIF-AHR cross-talk is limited to genes with regulatory regions that contain specific motifs and architectures, including the SRF, Sp-1, NF-kB, and AP-2 binding sites.
Abstract: The aryl hydrocarbon receptor (AHR) and hypoxia inducible factors (HIFs) are transcription factors that control the adaptive response to toxicants such as dioxins and decreases in available oxygen, respectively. The AHR and HIFs utilize the same heterodimeric partner, the aryl hydrocarbon nuclear translocator (ARNT) for proper function. This requirement raises the possibility that cross-talk exists between these critical signaling systems. Single gene and reporter assays have yielded conflicting results regarding the nature of the competition for ARNT. Therefore, to determine the extent of cross-talk between the AHR and HIFs, a comprehensive analysis was performed using global gene expression analysis. The results identified 767 and 430 transcripts that are sensitive to cobalt chloride and 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD) stimulation, respectively, with 308 and 176, respectively, exhibiting sensitivity to cross-talk. The overlap between these two sets consists of 33 unique transcripts, including the classic target genes CYP1A1, carbonic anhydrase IX, and those involved in lipid metabolism and coagulation. Computational analysis of the regulatory region of these genes identified complex relationships between HIFs, AHR, and their respective response elements as well as other DNA motifs, including the SRF, Sp-1, NF-kB, and AP-2 binding sites. These results suggest that HIF-AHR cross-talk is limited to genes with regulatory regions that contain specific motifs and architectures.