Check out our New Publishers' Select for Free Articles

Biochemical Pharmacology (v.77, #4)

Editorial Advisory Board (pp. iii).

Biological functions of the arylhydrocarbon receptor: Beyond induction of cytochrome P450s—Introduction to this special issue by Fumio Matsumura; Alvaro Puga; Chiharu Tohyama (pp. 473-473).

AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions by Fumiaki Ohtake; Yoshiaki Fujii-Kuriyama; Shigeaki Kato (pp. 474-484).

The arylhydrocarbon receptor (AhR) mediates the adverse effects of dioxins, including modulation of sex steroid hormone signaling. The role of AhR as a transcription factor is well described. AhR regulates the expression of target genes such as CYP1A1; however, the mechanisms of AhR function through other target-selective systems remain elusive. Accumulating evidence suggests that AhR modulates the functions of other transcription factors. The ligand-activated AhR directly associates with estrogen or androgen receptors (ERα or AR) and modulates their function both positively and negatively. This may, in part explain the sex steroid hormone-related adverse effects of dioxins. AhR has recently been shown to promote the proteolysis of ERα/AR through assembling a ubiquitin ligase complex, CUL4B^AhR. In the CUL4B^AhR complex, AhR acts as a substrate-recognition subunit to recruit ERα/AR. This action defines a novel role for AhR as a ligand-dependent E3 ubiquitin ligase. We propose that target-specific regulation of protein destruction, as well as gene expression, is modulated by environmental toxins through the E3 ubiquitin ligase activity of AhR.

Keywords: Abbreviations; AhR; arylhydrocarbon receptor; ERα; estrogen receptor; AR; androgen receptor; XRE; xenobiotic-responsive element; ERE; estrogen-responsive element; bHLH/PAS; basic helix-loop-helix/Per–Arnt–Sim; AF-1; autonomous activation function; E; ₂; 17β-estradiol; 3MC; 3-methylcholanthrene; βNF; β-naphthoflavone; CRL; cullin–RING ubiquitin ligase; SCF; Skp1–CUL1–F-box; CUL4B; cullin 4B; DDB1; damaged-DNA-binding protein 1AhR; Dioxin; Estrogen; Cullin 4B; Ubiquitin ligase

Regulation of constitutive and inducible AHR signaling: Complex interactions involving the AHR repressor by Mark E. Hahn; Lenka L. Allan; David H. Sherr (pp. 485-497).

The AHR is well known for regulating responses to an array of environmental chemicals. A growing body of evidence supports the hypothesis that the AHR also plays perhaps an even more important role in modulating critical aspects of cell function including cell growth, death, and migration. As these and other important AHR activities continue to be elucidated, it becomes apparent that attention now must be directed towards the mechanisms through which the AHR itself is regulated. Here, we review what is known of and what biological outcomes have been attributed to the AHR repressor (AHRR), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in multiple species. We discuss the structure and evolution of the AHRR and the dominant paradigm of a xenobiotic-inducible negative feedback loop comprised of AHR-mediated transcriptional up-regulation of AHRR and the subsequent AHRR-mediated suppression of AHR activity. We highlight the role of the AHRR in limiting AHR activity in the absence of xenobiotic AHR ligands and the important contribution of constitutively repressive AHRR to cancer biology. In this context, we also suggest a new hypothesis proposing that, under some circumstances, constitutively active AHR may repress AHRR transcription, resulting in unbridled AHR activity. We also review the predominant hypotheses on the molecular mechanisms through which AHRR inhibits AHR as well as novel mechanisms through which the AHRR may exert AHR-independent effects. Collectively, this discussion emphasizes the importance of this understudied bHLH-PAS protein in tissue development, normal cell biology, xenobiotic responsiveness, and AHR-regulated malignancy.

Keywords: Aryl hydrocarbon receptor; Aryl hydrocarbon receptor repressor; PAS proteins; Cancer; Toxicology

AHR-dependent misregulation of Wnt signaling disrupts tissue regeneration by Lijoy K. Mathew; Michel T. Simonich; Robert L. Tanguay (pp. 498-507).

The origins of molecular toxicology can be traced to understanding the interactions between halogenated aromatic hydrocarbons and the aryl hydrocarbon receptor (AHR). The physiological consequences of activation of the aryl hydrocarbon receptor are diverse, and we are just beginning to understand the importance of the AHR signal transduction pathway in homeostasis and disease. The many downstream targets that mediate these biological responses remain undefined. Studies have exploited the power of the zebrafish model to elucidate the mechanisms by which AHR activation disrupts biological signaling. Recent genomic analysis performed in a zebrafish tissue regeneration model revealed functional cross talk between AHR and the well-established Wnt/β-catenin signal transduction pathway. This review focuses on the development of the zebrafish model of AHR biology and the application of in vivo toxicogenomics to unravel molecular mechanisms.

Keywords: TCDD; Zebrafish; R-Spondin1

Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways by Thomas Haarmann-Stemmann; Hanno Bothe; Josef Abel (pp. 508-520).

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) is a widespread environmental pollutant, which causes a variety of severe health effects, e.g. immunosuppression, hepatotoxicity, and carcinogenesis. The main mediator of TCDD toxicity is the arylhydrocarbon receptor (AhR), which, upon activation, translocates into the nucleus and enforces gene expression. Since most of the pleiotropic effects caused by TCDD are associated with alterations in cell growth and differentiation, the analysis of the interference of the AhR with factors controlling these cellular functions seems to be a promising target regarding the prevention and treatment of chemical-provoked diseases. Cell growth and differentiation are regulated by numerous growth factors and cytokines. These multifunctional peptides promote or inhibit cell growth and regulate differentiation and other cellular processes, depending on cell-type and developmental stage. They are involved in the regulation of a broad range of physiological processes, including immune response, hematopoiesis, neurogenesis, and tissue remodeling. The complex network of growth factors and cytokines is accurately regulated and disturbances of this system are associated with adverse health effects. The molecular mechanisms by which the AhR interferes with this signaling network are multifaceted and the physiological consequences of this cross-talk are quite enigmatic. The investigation of this complex interaction is an exciting task, especially with respect to the recently described non-genomic and/or ligand-independent activities of AhR. Therefore, we summarize the current knowledge about the interaction of the AhR with three cytokine-/growth factor-related signal transducers – the epidermal growth factor (EGF) family, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) – with regard to pathophysiological findings.

Keywords: Abbreviations; AhR; arylhydrocarbon receptor; AIP; AhR interacting protein; ARNT; AhR nuclear translocator; Apaf1; apoptotic protease-activating factor 1; AREG; amphiregulin; bHLH; basic helix–loop–helix; B(; a; )P; benzo(; a; )pyrene; CDK; cyclin-dependent kinase; Cdkn; CDK inhibitor; COX-2; cyclooxygenase-2; CREB; cAMP-responsive element binding protein; CYP; cytochrome P450; E2F; elongation 2 factor; ECM; extracellular matrix; EGF; epidermal growth factor; EGFR; EGF receptor; EREG; epiregulin; ERK; extracellular signal-regulated kinase; FICZ; 6-formylindolo[3,2-; b; ]carbazole; hsp90; 90; kDa heat-shock protein; IL; interleukin; LTBP; latent TGF-β binding protein; MAPK; mitogen-activated protein kinase; MMP; matrix metalloproteinase; NF; naphtoflavone; PAH; polyaromatic hydrocarbon; PAI; plasminogen activators inhibitor; PAS; Per-ARNT-Sim; PKA; protein kinase A; RB; retinoblastoma; SARA; Smad anchor of receptor activation; TCDD; 2,3,7,8-tetrachlorodibenzo-; p; -dioxin; TβR; TGF-β receptor; TGF; transforming growth factor; TIMP; tissue inhibitor of metalloproteinase; TNF; tumor necrosis factor; UVB; ultraviolet-B; XRE; xenobiotic-responsive element

Aryl hydrocarbon receptor biology and xenobiotic responses in hematopoietic progenitor cells by Yoko Hirabayashi; Tohru Inoue (pp. 521-535).

Studying the biological functions of the aryl hydrocarbon receptor (AhR) other than its function in xenobiotic drug metabolism may answer the questions as to why AhR orthologues have long been conserved phylogenically widely in the animal kingdom, and why homologues have diverged from nonvertebrate species such as nematodes and drosophila to all the vertebrate species. In this review, we focused on the mechanism of longevity possibly derived from evolution of AhRs and compared the functional difference of hematopoietic progenitors between wild-type (AhR^+/+) mice and AhR-deficiencies (AhR^+/−, AhR^−/−). Particular advantages found in wild-type mice compared with AhR-deficiencies were as follows: first, higher antioxidative function in the hematopoietic microenvironment with low oxidative tension seemed to have developed with the evolution of AhR; second, primitive hematopoietic progenitor-cell-specific deceleration and dormancy of cell-cycle regulation may have developed also with AhR evolution, which keeps hematopoietic progenitor cell compartment dormant without extinction by continuous differentiation; third, the consequent evolution of genomic stabilization with a longer lifespan in wild-type mice developed with the evolution of AhR. Experimentally, mice showed a significant extension of lifespan in a gene-dosage-dependent manner with a delayed onset of leukemogenicity. Another possible additional advantage observed in wild-type mice, the mechanism of which is not yet clarified, is an improved efficiency of fertilization in wild-type mice as compared with AhR-deficiencies, which seems to have developed with the evolution of AhR. Four advantages altogether, including the anti-aging feature mentioned above may have induced the AhR molecule to diverge various of species in the animal kingdom.

Keywords: Abbreviations; AhRs; aryl hydrocarbon receptors; ARNT; aryl hydrocarbon receptor nuclear translocator; BM; bone marrow; BrdUrd; 5-bromo-2′-deoxyuridine (RN: 59-14-3); CFU; colony forming unit; CFU-E; colony forming unit-erythroid; CFU-GM; colony forming unit-granulocyte macrophage; CFU-S; colony forming unit in spleen; CYP; cytochrome P450; DCFH-DA; 2′,7′-dichlorodihydrofluorescein diacetate; Hif; hypoxia-inducing factor; KO; knockout; LKS fraction; a hematopoietic progenitor fraction with stem cell antigen (Sca1) and c-kit, without surface lineage-restricted antigen; MNU; 1-methyl-1-nitrosourea (RN: 684-93-5); PAS; the; Drosophila; period clock protein (PER), vertebrate ARNT, and; Drosophila; single-minded protein (SIM); PLTs; platelets; RBCs; red blood cells; ROS; reactive oxygen species; TCDD; 2,3,7,8-tetrachlorodibenzo-; p; -dioxin (RN: 1746-01-6); UV; ultraviolet; WBCs; white blood cells; XRE; xenobiotic responsive elementAryl hydrocarbon receptor; Hematopoietic stem/progenitor cells; Thioredoxin; Benzene; Gompertzean expressions

The aryl hydrocarbon receptor (AhR) pathway as a regulatory pathway for cell adhesion and matrix metabolism by Tiffany Kung; K.A. Murphy; L.A. White (pp. 536-546).

The aryl hydrocarbon receptor (AhR) is an orphan receptor in the basic helix–loop–helix PAS family of transcriptional regulators. Although the endogenous regulator of this pathway has not been identified, the AhR is known to bind and be activated by a variety of compounds ranging from environmental contaminants to flavanoids. The function of this receptor is still unclear; however, animal models indicate that the AhR is important for normal development. One hypothesis is that the AhR senses cellular stress and initiates the cellular response by altering gene expression and inhibiting cell cycle progression and that activation of the AhR by exogenous environmental chemicals results in the dysregulation of this normal function. In this review we will examine the role of the AhR in the regulation of genes and proteins involved in cell adhesion and matrix remodeling, and discuss the implications of these changes in development and disease. In addition, we will discuss evidence suggesting that the AhR pathway is responsive to changes in matrix composition as well as cell–cell and cell–matrix interactions.

Keywords: AhR; Extracellular matrix (ECM); Matrix metalloproteinase (MMP); 2,3,7,8-tetrachlorodibenzo-; p; -dioxin (TCDD); Development

The role of the aryl hydrocarbon receptor in the female reproductive system by Isabel Hernández-Ochoa; Bethany N. Karman; Jodi A. Flaws (pp. 547-559).

In recent years, many studies have emphasized how changes in aryl hydrocarbon receptor (AHR)-mediated gene expression result in biological effects, raising interest in this receptor as a regulator of normal biological function. This review focuses on what is known about the role of the AHR in the female reproductive system, which includes the ovaries, Fallopian tubes or oviduct, uterus and vagina. This review also focuses on the role of the AHR in reproductive outcomes such as cyclicity, senescence, and fertility. Specifically, studies using potent AHR ligands, as well as transgenic mice lacking the AHR-signaling pathway are discussed from a viewpoint of understanding the endogenous role of this ligand-activated transcription factor in the female reproductive lifespan. Based on findings highlighted in this paper, it is proposed that the AHR has a role in physiological functions including ovarian function, establishment of an optimum environment for fertilization, nourishing the embryo and maintaining pregnancy, as well as in regulating reproductive lifespan and fertility. The mechanisms by which the AHR regulates female reproduction are poorly understood, but it is anticipated that new models and the ability to generate specific gene deletions will provide powerful experimental tools for better understanding how alterations in AHR pathways result in functional changes in the female reproductive system.

Keywords: Abbreviations; 3β-HSD; 3β-hydroxysteroid dehydrogenase; AHR; aryl hydrocarbon receptor; AHREs; AHR response elements; Ahr; null mice; ARNT; aryl hydrocarbon nuclear translocator; Aromatase; cytochrome P450c19; Bax; Bcl2-associated X protein; Bcl2; B-cell leukemia/lymphoma 2; CCND2; cyclin D2; CDK4; cyclin-dependent kinase 4; CL; corpus luteum; CLs; corpora lutea; COX2; cyclo-oxygenase-2; DMBA; 7,12-dimethylbenz[a]anthracene; DMBA-DHD; 9,10-dimethylbenz[a]anthracene-3,4-dihydrodiol; E2; estradiol; eCG; equine chorionic gonadotropin; ED; embryonic day; ESR; estrogen receptor 1 (alpha); ESR2; estrogen receptor 2 (beta); FSH; follicle stimulating hormone; FSHR; follicle stimulating hormone receptor; GnRH; gonadotropin releasing hormone; hCG; human chorionic gonadotropin; IP; intraperitoneal; LH; luteinizing hormone; LHCGR; luteinizing hormone receptor; P450c17; cytochrome P450 17α-hydroxylase; P450scc; cytochrome P450 cholesterol side-chain cleavage; PCB; polychlorinated biphenyl; PCNA; proliferating cell nuclear antigen; PND; postnatal days; PR; progesterone receptor; RT-PCR; real-time polymerase chain reaction; TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin; WT; wild-typeAryl hydrocarbon receptor; Ovary; Uterus; Vagina; Oviduct; Female reproduction

Crosstalk between the AHR signaling pathway and circadian rhythm by Shigeki Shimba; Yuichi Watabe (pp. 560-565).

In this chapter, we review the crosstalk between the AHR signaling pathway and molecular clock system in mammals.In mammals, circadian rhythm is observed in most physiological functions including behavior, metabolism, cell growth, and immune responses. Circadian rhythm is regulated by a transcriptional feedback loop, and the transcription factor called “Brain Muscle ARNT-like protein 1 (BMAL1)” is a master regulator of this system. Because of its structural similarity to ARNT, a partner of AHR, BMAL1 is also referred as ARNT3. This structural feature of BMAL1 suggests that the activation of the AHR signaling pathway may influence the regulation of circadian rhythm. Several studies have shown that the expression levels of AHR display diurnal variation in many tissues. This circadian variation of AHR means that the pharmacological effects of AHR agonists vary according to the time of administration. AHR agonist administration results in a disruption of circadian rhythm with regard to behavior, immune cell proliferation, etc. As such, understanding the crosstalk between the AHR signaling and circadian rhythm may provide a new insight into TCDD actions.

Keywords: Aryl hydrocarbon receptor; Brain Muscle ARNT-like protein 1; Circadian rhythm

AHR signaling in prostate growth, morphogenesis, and disease by Chad M. Vezina; Tien-Min Lin; Richard E. Peterson (pp. 566-576).

Most evidence of aryl hydrocarbon receptor (AHR) signaling in prostate growth, morphogenesis, and disease stems from research using 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) to pharmacologically activate the AHR at various stages of development. This review discusses effects of TCDD on prostate morphogenesis and highlights interactions between AHR and other signaling pathways during normal and aberrant prostate growth. Although AHR signaling modulates estrogen and androgen signaling in other tissues, crosstalk between these steroid hormone receptors and AHR signaling cannot account for actions of TCDD on prostate morphogenesis. Instead, the AHR appears to act within a cooperative framework of developmental signals to regulate timing and patterning of prostate growth. Inappropriate activation of AHR signaling as a result of early life TCDD exposure disrupts the balance of these signals, impairs prostate morphogenesis, and has an imprinting effect on the developing prostate that predisposes to prostate disease in adulthood. Mechanisms of AHR signaling in prostate growth and disease are only beginning to be unraveled and recent studies have revealed its interactions with WNT5A, retinoic acid, fibroblast growth factor 10, and vascular endothelial growth factor signaling pathways.

The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations by Kameshwar P. Singh; Fanny L. Casado; Lisa A. Opanashuk; Thomas A. Gasiewicz (pp. 577-587).

The aryl hydrocarbon receptor (AhR) is known mainly as the mediator for the toxicity of certain xenobiotics. However, there is also much information to indicate that this transcription factor has important biological functions. Here we review the evidence that the AhR has a significant role in the regulation of hematopoietic stem cells (HSCs). Data to support this come from studies with xenobiotic AhR ligands, phenotypic analyses of mice lacking AhR, examining the presence and regulation of the AhR within HSCs, knowledge of genes and signaling pathways regulated by the AhR, and investigations of hematopoietic disorders. Based on this information, we hypothesize that AhR expression is necessary for the proper maintenance of quiescence in HSCs, and that AhR down-regulation is essential for “escape” from quiescence and subsequent proliferation of these cells. This implicates the AhR as a negative regulator of hematopoiesis with a function of curbing excessive or unnecessary proliferation. This provides an important advantage by preventing the premature exhaustion of HSCs and sensitivity to genetic alterations, thus preserving HSC function and long-term multi-lineage generation over the lifespan of the organism. This also implicates a role of the AhR in aging processes. AhR dysregulation may result in the altered ability of HSCs to sense appropriate signals in the bone marrow microenvironment leading to hematopoietic disease. It is also reasonable to hypothesize that this protein has an important function in the regulation of other tissue stem cell populations. Suggestive evidence is consistent with a role in skin and neural stem cells.

Keywords: Abbreviations; 5-FU; 5-fluorouracil; AhR; aryl hydrocarbon receptor; AhRE; aryl hydrocarbon receptor response element; BrdU; bromodeoxyuridine; CFU-G; colony-forming unit granulocyte; CFU-GM; CFU-granulocyte/megakaryocyte; CFU-M; CFU-macrophage; CLP; common lymphoid progenitor; CMP; common myeloid progenitor; GNP; granule neuron progenitor; HPCs; hematopoietic progenitor cells; HPP-CFC; high proliferative potential-colony forming cells; HSCs; hematopoietic stem cells; LSK; HSC-enriched lineage-negative, cKit-positive, Sca-1-positive cells; LT-HSC; long-term repopulating HSCs; MPP; mulipotent progenitors; NSC; neuroepithelial stem cell; ST-HSCs; short-term repopulating HSCs; TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxinAryl hydrocarbon receptor; Stem cells; Hematopoietic stem cells; Progenitor cells

AhR protein trafficking and function in the skin by Togo Ikuta; Takeshi Namiki; Yoshiaki Fujii-Kuriyama; Kaname Kawajiri (pp. 588-596).

Because aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, its nuclear translocation in response to ligands may be directly linked to transcriptional activation of target genes. We have investigated the biological significance of AhR from the perspective of its subcellular localization and revealed that AhR possesses a functional nuclear localization signal (NLS) as well as a nuclear export signal (NES) which controls the distribution of AhR between the cytoplasm and nucleus. The intracellular localization of AhR is regulated by phosphorylation of amino acid residues in the vicinity of the NLS and NES. In cell culture systems, cell density affects not only its intracellular distribution of AhR, but also its transactivation activity of the target genes such as transcriptional repressor Slug, which is important for the induction of epithelial–mesenchymal transitions. These effects of AhR observed in cultured cells are proposed to be reflected on the in vivo response such as morphogenesis and tumor formation.This review summarizes recent work on the control mechanism of AhR localization and progress in understanding the physiological role of AhR in the skin. We propose that AhR is involved in normal skin formation during fetal development as well as in pathological states such as epidermal wound healing and skin carcinogenesis.

Keywords: Subcellular localization; Cell–cell contact; Epithelial–mesenchymal transitions; Wound healing; Carcinogenesis

The immune phenotype of AhR null mouse mutants: Not a simple mirror of xenobiotic receptor over-activation by Charlotte Esser (pp. 597-607).

Intrinsic and induced cell differentiation and the cellular response to endogenous and exogenous signals are hallmarks of the immune system. Specific and common signalling cascades ensure a highly flexible and adapted response. Increasing evidence suggests that gene modulation by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is an important part of these processes. For decades the AhR has been studied mainly for its toxic effects after artificial activation by man-made chemical pollutants such as dioxins. These studies gave important, albeit to some extent skewed, evidence for a mechanistic link between the AhR and the immune system. AhR null mutants and other mutants of the AhR signalling pathway have been generated and used to analyse the physiological function of the AhR, including for the developing and antigen-responding immune system. In this review I look at the natural immunological function(s) of the AhR.

Keywords: Abbreviations; AhR; aryl hydrocarbon receptor; ARNT; AhR nuclear translocator; DC; dendritic cells; DN; double negative; DRE; dioxin responsive element; OVA; ovalbumin; ConA; concanavalin A; PAH; polycyclic aromatic hydrocarbon; TCDD; 2,3,7,8-tetrachloro-dibenzo-p-dioxin; XRE; xenobiotic response elementArylhydrocarbon receptor; Knock-out mice; Immunity; IL-17; Cytokine balance

The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects by Fumio Matsumura (pp. 608-626).

Evidence has been accumulating to indicate that the current classical model of dioxin's action based on the ligand-activated aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) dimer directly activating its target genes is not robust enough to explain many of the major toxic effects of this compound. In this review, efforts have been made to analyze the results of recent investigations in our laboratory in comparison to already existing evidence on the patterns of toxic actions of dioxin (=TCDD) from other laboratories from a specific viewpoint of elicitation of cellular inflammatory signaling by the ligand-activated AHR. The most salient features of the inflammatory action of TCDD are that its triggering events, such as the rapid increase in intracellular Ca²⁺ concentration, enzymatic activation of cytosolic phospholipase A2 (cPLA2) and that of Cox-2 are taking place through the nongenomic action of the ligand-activated AHR. This nongenomic pathway does not require ARNT. Therefore, this inflammation pathway is clearly discernable from the classical, genomic action pathway. The effect of such a nongenomic signaling persists for long time periods as shown by recent findings that artificial suppression of the early triggering events of this pathway, such as via suppression of cPLA2, Cox-2, or Src kinase indeed causes significant reduction of manifestations of hallmark toxicities of TCDD such as wasting syndrome and hydronephrosis. Together, the evidence strongly support the notion that the inflammatory action of the ligand-activated AHR that is mediated by the nongenomic pathway plays the major role in the inflammation inducing actions of dioxin-like chemicals.

Keywords: Abbreviations; TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin; AHR; aryl hydrocarbon receptor; ARNT; aryl hydrocarbon receptor nuclear translocator; Cox-2; cyclooxygenase-2; MMP-2; matrix metalloproteinase-2; CSF-1; colony stimulating factor-1; cPLA2; cytosolic phospholipase A2; DRE; dioxin responsive element; EGF; epidermal growth factor; EGFR; epidermal growth factor receptor; TNFα; tumor necrosis facto alpha; AP-1; activator protein-1; C/EBP; CCAAT enhancer binding protein; PKA; protein kinase A; IBMX; isobutylmethylxanthine; CYP19; cytochrome P450 19 or aromatase; H89; N-[2-((p-Bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide; MAFP; methylarachidonyl fluorophosphonate; EGTA/AM; EGTA-acetoxymethyl ester; AACOCF3; arachidonyl trifluoromethyl ketone; [Ca; ²⁺; ]; _i; intracellular concentration of free calcium ion; NIEHS; National Institute of Environmental Health Sciences; TLR; Toll-like receptor; LPS; lipopolysaccharides; siRNA; small interfering RNA; GLUT4; glucose transporter 4; LPL; lipoproteinlipase; EMSA; gel electrophoresis mobility shift assayAh receptors; Nongenonic pathway; Toxic action of TCDD; Inflammation in toxicity of TCDD; Rapid activation of cPLA2 and Cox-2

Role of cAMP in mediating AHR signaling by Barbara Oesch-Bartlomowicz; Franz Oesch (pp. 627-641).

Regulation of the nuclear import of many transcription factors represents a step in gene regulation which is crucial for a number of cellular processes. The aryl hydrocarbon receptor (AHR), a basic helix–loop–helix protein of the PAS (PER-ARNT-SIM) family of transcriptional regulators is a cytosol-associated and ligand-activated receptor. The environmental toxin dioxin binds with high affinity to AHR rendering it nuclear and leading to the activation of AHR sensitive genes. However, the fact, that the AHR mediates a large variety of physiological events without the involvement of any known exogenous ligand, including liver and vascular system development, maturation of the immune system, regulation of genes involved in cellular growth, cell differentiation and circadian rhythm, speaks for an important role of AHR in cell biology independent of the presence of an exogenous ligand. Different approaches were applied to study mechanism(s) which render AHR nuclear and design its function in absence of exogenous ligands. We found that AHR is sensitive to cAMP signaling mediated by cAMP-dependent protein kinase (PKA) which fundamentally differs from AHR signaling mediated by the exogenous ligand dioxin. It has been shown that PKA mediated signaling can be confined by compartmentalization of signaling components in microdomains conferring specificity to signaling by the ubiquitous second messenger cAMP. Moreover, A-kinase-anchoring proteins (AKAPs) and newly discovered cAMP receptors, Epac ( exchange protein directly activated by cAMP), may give us a further chance to enter into new dimensions of cAMP signal transmissions that potentially may bring us closer to AHR physiology.

Keywords: Aryl hydrocarbon receptor; cyclic AMP; Protein kinase A; Nuclear translocation; Signal transduction; Dioxin toxicity; Phosphorylation

The aryl hydrocarbon receptor is a modulator of anti-viral immunity by Jennifer L. Head; B. Paige Lawrence (pp. 642-653).

Although immune modulation by AhR ligands has been studied for many years, the impact of AhR activation on host defenses against viral infection has not, until recently, garnered much attention. The development of novel reagents and model systems, new information regarding anti-viral immunity, and a growing appreciation for the global health threat posed by viruses have invigorated interest in understanding how environmental signals affect susceptibility to and pathological consequences of viral infection. Using influenza A virus as a model of respiratory viral infection, recent studies show that AhR activation cues signaling events in both leukocytes and non-immune cells. Functional alterations include suppressed lymphocyte responses and increased inflammation in the infected lung. AhR-mediated events within and extrinsic to hematopoietic cells has been investigated using bone marrow chimeras, which show that AhR alters different elements of the immune response by affecting different tissue targets. In particular, suppressed CD8⁺ T cell responses are due to deregulated events within leukocytes themselves, whereas increased neutrophil recruitment to and IFN-γ levels in the lung result from AhR-regulated events extrinsic to bone marrow-derived cells. This latter discovery suggests that epithelial and endothelial cells are overlooked targets of AhR-mediated changes in immune function. Further support that AhR influences host cell responses to viral infection are provided by several studies demonstrating that AhR interacts directly with viral proteins and affects viral latency. While AhR clearly modulates host responses to viral infection, we still have much to understand about the complex interactions between immune cells, viruses, and the host environment.

Keywords: Abbreviations; AhR; aryl hydrocarbon receptor; AhR; ^+/+; AhR wild-type; AhR; ^−/−; AhR deficient; AhRE; AhR response element; Arnt; AhR nuclear translocator; C/EBP-β; CCAAT-enhancer box binding protein beta; CMV; Cytomegalovirus; CTL; cytotoxic T lymphocytes; DC; dendritic cell; EBNA-3; EBV nuclear antigen; EBV; Epstein-Barr virus; ER-α; estrogen receptor alpha; HIF-1β; hypoxia inducible factor-1 beta; HIV; Human immunodeficiency virus; HSV-1; Herpes simplex virus-1; IFN-γ; Interferon gamma; iNOS; inducible nitric oxide synthase; MHC; major histocompatability complex; NF-κB; nuclear factor kappa B; NK cell; natural killer cell; NO; nitric oxide; PRR; pattern recognition receptor; RSV; Respiratory syncytial virus; TCDD; 2,3,7,8-tetrachlorodibenzo-; p; -dioxin; Th17; IL-17 producing T helper cells; T; _reg; CD4; ⁺; CD25; ⁺; regulatory T cells; XAP-2; X-associated protein 2Influenza virus; Neutrophils; T cells; Immune response; Lung

Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster by Manabu Nukaya; Christopher A. Bradfield (pp. 654-659).

A thorough DNA sequence analysis reveals that the mouse Cyp1a1 and Cyp1a2 loci are located with coding directions opposite to each other. The two genes are separated by approximately 13.9kb of genomic DNA containing no open reading frames ( mCyp1a1_1a2 junction). Within the mCyp1a1_1a2 junction, eight consensus dioxin responsive elements (DREs) are present and seven of the eight DREs located less than 1.4kb upstream from the Cyp1a1 transcriptional start site. The genomic structure of mouse Cyp1a1 and Cyp1a2 loci is similar to that of human CYP1A1 and CYP1A2 loci. In the human CYP1A1 and CYP1A2 are also arranged in a head to head orientation and separated by a 23kb genome junction ( hCyp1A1_1A2). Comparative sequence analysis between these two genomic junctions demonstrated that the 1.4kb upstream region from the transcriptional start site of mouse Cyp1a1 was highly conserved with that of human CYP1A1. In contrast, there are no conserved DREs in the proximal upstream region of Cyp1a2. The “head to head” genomic structure and position of the DREs cluster region near the Cyp1a1 gene on Cyp1a1_1a2 were confirmed in cattle, dog and rat genome. These results suggest that the conservation of genomic structure of Cyp1a1 and Cyp1a2 genes, and the DREs cluster are important in mammalian biology.

Keywords: Abbreviations; AHR; aryl hydrocarbon receptor; ARNT; AHR nuclear translocator; BAC; bacterial artificial chromosome; DRE; dioxin responsive element; CYP; cytochrome P450; dioxin; 2,3,7,8-tetrachlorodibenzo-; p; -dioxin, genomic junction region of; Cyp1a1; and; Cyp1a2; ,; Cyp1a1_1a2; kb; kilo basepair(s); PAHs; polycyclic aromatic hydrocarbonsCytochrome P450; Cyp1a1; Cyp1a2; DRE; AHR; Dioxin

Dioxin-induced toxicity on vascular remodeling of the placenta by Ryuta Ishimura; Takashige Kawakami; Seiichiroh Ohsako; Chiharu Tohyama (pp. 660-669).

Arylhydrocarbon receptor (AhR) activated by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) triggers its downstream signaling pathway to exert adverse effects on vasculature development, which can be initiated by vasculogenesis, followed by angiogenesis, or vascular remodeling, in a variety of animals including avians, piscines and mammals. The placenta, a mammalian organ rich in vasculature, consists of endothelial and trophoblast cells of fetal origin, which proliferate and differentiate under hypoxic condition in the uterine horn. Our studies demonstrated that vascular remodeling occurs prominently in the placenta of the control Holtzman rat strain during the late period of gestation, and induces changes in cell shape and elimination by apoptosis of trophoblasts. As a result, the net volumes of both maternal and fetal blood in the placenta increase to cope with the essential requirements of oxygen and nutrients in the late period of gestation. On the other hand, in utero exposure to TCDD markedly suppressed the development of sinusoids and trophoblast cells and the apoptosis of trophoblast cells with a concomitant increase in the incidence of fetal death under hypoxic condition. A crosstalk between the hypoxia-inducible factor (HIF)-mediated pathway and AhR-mediated pathway is considered to play an important role in this physiological process. No such changes were observed in the Sprague–Dawley rat strain that turned out to have an AhR conformation identical to that of the Holtzman rat strain. In this commentary, we will discuss a possible link of the TCDD toxicities with the AhR signaling pathway and gestation-related diseases.

Keywords: Abbreviations; AhR; arylhydrocarbon receptor; ARNT; aryl hydrocarbon receptor nuclear translocator; GD; gestation day; HIF; hypoxia-inducible factor; HUVECs; human umbilical vein endothelial cells; TCDD; 2,3,7,8-tetrachlorodibenzo-; p; -dioxinAngiogenesis; Arylhydrocarbon receptor; Hypoxia; Placenta; Vasculogenesis

Ah receptor and NF-κB interplay on the stage of epigenome by Yanan Tian (pp. 670-680).

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family. Its ligands include many natural and synthetic compounds, some of which, such as polyhalogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons, are important environmental contaminants. NF-κB is a pleiotropic factor that regulates many physiological and pathophysiological processes including the immune and inflammatory responses. In the past decade, accumulating evidence suggests close interactions between AhR and NF-κB pathways, and these interactions are potentially important mechanisms for many pathological processes such as the chemical-induced immune dysfunctions, carcinogenesis and alteration of xenobiotic metabolism and disposition. AhR–NF-κB interaction has become a mechanistic linchpin linking certain pathological responses induced by environmental insults. Furthermore, the AhR–NF-κB interaction provides basis for therapeutic applications of certain AhR ligands to treat human diseases. The effects of AhR–NF-κB on the epigenome are an important area that is not well understood. In this review, I highlight current research regarding the AhR–NF-κB(RelA) interactions with emphasis on the epigenetic impacts of these interactions on chromatin modifications and transcription elongation control.

Keywords: Ah receptor; NF-κB; Epigenetics; Inflammation; Dioxin

Activation of the aryl hydrocarbon receptor by TCDD inhibits senescence: A tumor promoting event? by S. Ray; H.I. Swanson (pp. 681-688).

Activation of the aryl hydrocarbon receptor (AHR) by the agonist, 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) has been shown to promote tumor formation in both liver and skin. In the liver, but not the skin, the AHR-mediated events that contribute to TCDD’s tumor promoting activities have been studied in some detail and are thought to involve perturbation of cell fate processes. However, studies performed using cultured cells have often resulted in apparent contradictory results indicating that the impact of TCDD on cell fate processes may be cell context dependent. We and others have shown that in primary cultured keratinocytes TCDD increases post-confluent proliferation and increases late differentiation. Further, our studies performed in these cells indicate that TCDD can also inhibit culture-induced senescence. While senescence, a permanent cell cycle arrest, is emerging as an important process regulated by oncogenes and considered to be of therapeutic importance, its role with respect to TCDD/AHR mediated tumor promotion has not been fully considered. The intent of this article is to focus primarily on senescence as a cell process relevant to skin tumorigenesis and explore the idea that the inhibition of senescence by TCDD could be an important mechanism by which it may exert its tumor promoting effects in the skin.

Keywords: Abbreviations; AHR; aryl hydrocarbon receptor; MNF; 3′-methoxy-4′-nitroflavone; TCDD; 2,3,7,8-tetrachlorodibenzo-; p; -dioxin; ROS; reactive oxygen species; TGF-β; transforming growth factor beta; UVB; ultraviolet light BAryl hydrocarbon receptor; Keratinocytes; 2,3,7,8-Tetrachlorodibenzo-; p; -dioxin; Senescence; Tumorigenesis

Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor by Christoph Köhle; Karl Walter Bock (pp. 689-699).

Coordinate regulation of Phase I and II drug-metabolizing enzymes and conjugate transporters by nuclear receptors suggests that these proteins evolved to an integrated biotransformation system. Two major groups of ligand-activated nuclear receptors/xenosensors evolved: the Ah receptor (activated by aryl hydrocarbons and drugs such as omeprazole) and type 2 steroid receptors such as PXR and CAR, activated by drugs such as rifampicin, carbamazepin and phenytoin. It is increasingly recognized that there is considerable cross-talk between these xenosensors. Therefore, an attempt was made to discuss biotransformation by the Ah receptor together with that of PXR and CAR. Due to considerable species differences the emphasis is on human biotransformation. Agonists coordinately induce biotransformation due to common xenosensor-binding response elements in the regulatory region of target genes. However, whereas different groups of xenobiotics appear to more selectively stimulate CYPs (Phase I), their regulatory control largely converged in modulating Phase II metabolism and transport. Biotransformation appears to be tightly controlled to achieve efficient homeostasis of endobiotics and detoxification of dietary phytochemicals, but nuclear receptor agonists may also lead to potentially harmful drug interactions.

Keywords: Abbreviations; AHR; aryl hydrocarbon receptor; ARE; antioxidant response element; BaP; benzo[; a; ]pyrene; BCRP; breast cancer resistance protein; BSEP; bile salt export pump; CAR; constitutive androstane receptor; FXR; farsenoid X receptor; GR; glucocorticoid receptor; LXR; liver X receptor; MDR; multidrug resistance protein; MRP; multidrug resistance-associated protein; Nrf2; nuclear factor erythroid 2-related factor; NTCP; sodium taurocholate cotransporting polypeptide; OATP; organic anionic transport proteins; OST; organic anion steroid transporter; PAH; polycyclic aromatic hydrocarbon; PBREM; phenobarbital responsive enhancer module; PPAR; peroxisome proliferator-activated receptor; PXR; pregnane X receptor; UGT; UDP-glucuronosyltransferase; t; BHQ; tert; butylhydroquinone; XRE; xenobiotic response elementAh receptor; Pregnane X receptor; Drug metabolism; Conjugate transporters; Cytochrome P450s; UDP-glucuronosyltransferases

Fitting a xenobiotic receptor into cell homeostasis: How the dioxin receptor interacts with TGFβ signaling by Aurea Gomez-Duran; Jose M. Carvajal-Gonzalez; Sonia Mulero-Navarro; Belen Santiago-Josefat; Alvaro Puga; Pedro M. Fernandez-Salguero (pp. 700-712).

As our knowledge on the mechanisms that control cell function increases, more complex signaling pathways and quite intricate cross-talks among regulatory proteins are discovered. Establishing accurate interactions between cellular networks is essential for a healthy cell and different alterations in signaling are known to underline human disease. Transforming growth factor beta (TGFβ) is an extracellular cytokine that regulates such critical cellular responses as proliferation, apoptosis, differentiation, angiogenesis and migration, and it is assumed that the latency-associated protein LTBP-1 plays a relevant role in TGFβ targeting and activation in the extracellular matrix (ECM). The dioxin receptor (AhR) is a unique intracellular protein long studied because of its critical role in xenobiotic-induced toxicity and carcinogenesis. Yet, a large set of studies performed in cellular systems and in vivo animal models have suggested important xenobiotic-independent functions for AhR in cell proliferation, differentiation and migration and in tissue homeostasis. Remarkably, AhR activity converges with TGFβ-dependent signaling through LTBP-1 since cells lacking AhR expression have phenotypic alterations that can be explained, at least in part, by the coordinated regulation of both proteins. Here, we will discuss the existence of functional interactions between AhR and TGFβ signaling. We will focus on regulatory and functional aspects by analyzing how AhR status determines TGFβ activity and by proposing a mechanism through which LTBP-1, a novel AhR target gene, mediates such effects. We will integrate ECM proteases in the AhR-LTBP-1-TGFβ axis and suggest a model that could help explain some in vivo phenotypes associated to AhR deficiency.

Keywords: Abbreviations; AhR; aryl hydrocarbon (dioxin) receptor; ARNT; aryl hydrocarbon receptor nuclear translocator; CREB; cAMP responsive element-binding protein; ECM; extracellular matrix; FGM; immortalized mouse fibroblasts; HDAC; histone deacetylase; LTBP-1; latent transforming growth factor-binding protein 1; MEF; mouse embryonic fibroblasts; TGFβ; transforming growth factor βDioxin receptor; TGFβ; LTBP-1; Liver fibrosis

The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways by Alvaro Puga; Ci Ma; Jennifer L. Marlowe (pp. 713-722).

Exposure to toxic polycyclic aromatic hydrocarbons raises a number of toxic and carcinogenic responses in experimental animals and humans mediated for the most part by the aryl hydrocarbon – or dioxin – receptor (AHR). The AHR is a ligand-activated transcription factor whose central role in the induction of drug-metabolizing enzymes has long been recognized. For quite some time now, it has become clear that the AHR also functions in pathways outside of its role in detoxification and that perturbation of these pathways by xenobiotic ligands may be an important part of the toxicity of these compounds. AHR activation by some of its ligands participates among others in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, cross-talk within the RB/E2F axis and mobilization of crucial calcium stores. Ultimately, the effect of a particular AHR ligand may depend as much on the adaptive interactions that it established with pathways and proteins expressed in a specific cell or tissue as on the toxic responses that it raises.

Keywords: Aryl hydrocarbon receptor; Phosphorylation; Mitogen-activated kinases; Cell cycle progression; Differentiation; Apoptosis; E2F; RB

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling by Simone Kobe de Oliveira; Albert Smolenski (pp. 723-733).

The aryl hydrocarbon receptor (AHR) is a major transcription factor regulated by different mechanisms. The classical view of AHR activation by xenobiotics needs to be amended by recent findings on the regulation of AHR by endogenous ligands and by crosstalk with other signaling pathways. In the cytosol the AHR recruits a large number of binding partners, including HSP90, p23, XAP2 and the ubiquitin ligases cullin 4B and CHIP. Furthermore, XAP2 binds the cyclic nucleotide phosphodiesterases PDE2A and PDE4A5. PDE2A inhibits nuclear translocation of AHR suggesting an important regulatory role of cyclic nucleotides in AHR trafficking. Signaling involving cAMP is organized in subcellular compartments and a distinct cAMP compartment might be required for proper AHR mobility and function. We conclude that the AHR complex integrates ligand binding and cyclic nucleotide signaling to generate an adequate transcriptional response.

Keywords: ARA9; AIP; PDE; cAMP; cGMP; Dioxin

A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-κB family by Christoph F.A. Vogel; Fumio Matsumura (pp. 734-745).

The discovery of the new crosstalk between the aryl hydrocarbon receptor (AhR) and the NF-κB subunit RelB may extend our understanding of the biological functions of the AhR and at the same time raises a number of questions, which will be addressed in this review. The characteristics of this interaction differ from that of AhR with RelA in that the latter appears to be mostly negative unlike the collaborative interactions of AhR/RelB. The AhR/RelB dimer is capable of binding to DNA response elements including the dioxin response element (DRE) as well as NF-κB binding sites supporting the activation of target genes of the AhR as well as NF-κB pathway. Further studies show that AhR/RelB complexes can be found not only in lymphoid cells but also in a human hepatoma cell line (HepG2) or breast cancer cell line (MDA-MB-231). RelB has been implicated in carcinogenesis of breast cancer for instance and RelB is known to be a critical factor for the function and differentiation of dendritic cells; interestingly the participation of AhR in both processes has been suggested recently, which offers the great potential to expand the scope of the physiological roles of the AhR. There is evidence indicating that RelB may serve as a pro-survival factor, including its ability to promote “inflammation resolution” besides the association of RelB with inflammatory disorders. Based on such information, a hypothesis has been proposed in this review that AhR together with RelB functions as a coordinator of inflammatory responses.

Keywords: Abbreviations; AhR; aryl hydrocarbon receptor; ARNT; AhR nuclear translocator; COX-2; Cyclooxygenase 2; DC; dendritic cell; DRE; dioxin response element; FICZ; 6-formylindolo[3,2-b]carbazole; IDO; indoleamine-2,3-dioxygenase; IL-8; Interleukin 8; IFN; Interferon; RelBAhRE; RelB/AhR response element; PKA; protein kinase A; TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin; T; _reg; regulatory T cells; XAP2; X-associated protein 2AhR; IDO; IL-8; NF-kappaB RelB; TCDD

AHR-mediated immunomodulation: The role of altered gene transcription by Nancy I. Kerkvliet (pp. 746-760).

The immune system is a sensitive target for aryl hydrocarbon receptor (AHR)-mediated transcriptional regulation. Most of the cells that participate in immune responses express AHR protein, and many genes involved in their responses contain multiple DRE sequences in their promoters. However, the potential involvement of many of these candidate genes in AHR-mediated immunomodulation has never been investigated. Many obstacles to understanding the transcriptional effects of AHR activation exist, owing to the complexities of pathogen-driven inflammatory and adaptive immune responses, and to the fact that activation of AHR often influences the expression of genes that are already being regulated by other transcriptional events in responding cells. Studies with TCDD as the most potent, non-metabolized AHR ligand indicate that AHR activation alters many inflammatory signals that shape the adaptive immune response, contributing to altered differentiation of antigen-specific CD4⁺ T helper (TH) cells and altered adaptive immune responses. With TCDD, most adaptive immune responses are highly suppressed, which has been recently linked to the AHR-dependent induction of CD4⁺CD25⁺ regulatory T cells. However activation of AHR by certain non-TCDD ligands may result in other immune outcomes, as a result of metabolism of the ligand to active metabolites or to unknown ligand-specific effects on AHR-mediated gene transcription. Based on studies using AHR^−/− mice, evidence for a role of endogenous AHR ligands in regulation of the immune response is growing, with bilirubin and lipoxinA4 representing two promising candidates.

Sections

Personal tools

Biochemical Pharmacology (v.77, #4)

Sections

Personal tools

Local resources

Biochemical Pharmacology (v.77, #4)