CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis.

The activation marker CD69 is expressed by skin γδ T cells. Here we found that CD69 controlled the aryl hydrocarbon receptor (AhR)-dependent secretion of interleukin 22 (IL-22) by γδ T cells, which contributed to the development of psoriasis induced by IL-23. CD69 associated with the aromatic-amino-acid-transporter complex LAT1-CD98 and regulated its surface expression and uptake of L-tryptophan (L-Trp) and the intracellular quantity of L-Trp-derived activators of AhR. In vivo administration of L-Trp, an inhibitor of AhR or IL-22 abrogated the differences between CD69-deficient mice and wild-type mice in skin inflammation. We also observed LAT1-mediated regulation of AhR activation and IL-22 secretion in circulating Vγ9(+) γδ T cells of psoriatic patients. Thus, CD69 serves as a key mediator of the pathogenesis of psoriasis by controlling LAT1-CD98-mediated metabolic cues.

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022.

The aryl hydrocarbon receptor (AHR) is a sensor of low-molecular-weight molecule signals that originate from environmental exposures, the microbiome, and host metabolism. Building upon initial studies examining anthropogenic chemical exposures, the list of AHR ligands of microbial, diet, and host metabolism origin continues to grow and has provided important clues as to the function of this enigmatic receptor. The AHR has now been shown to be directly involved in numerous biochemical pathways that influence host homeostasis, chronic disease development, and responses to toxic insults. As this field of study has continued to grow, it has become apparent that the AHR is an important novel target for cancer, metabolic diseases, skin conditions, and autoimmune disease. This meeting attempted to cover the scope of basic and applied research being performed to address possible applications of our basic knowledge of this receptor on therapeutic outcomes.

Aryl hydrocarbon receptor controls skin homeostasis, regeneration, and hair follicle cycling by adjusting epidermal stem cell function.

Skin integrity requires constant maintenance of a quiescent, yet responsive, population of stem cells. While interfollicular epidermal progenitors control normal homeostasis, hair follicle stem cells residing within the bulge provide regenerative potential during hair cycle and in response to wounding. The aryl hydrocarbon receptor (AhR) modulates cell plasticity and differentiation and its overactivation results in severe skin lesions in humans. However, its physiological role in skin homeostasis and hair growth is unknown. Reconstitution assays grafting primary keratinocytes and dermal fibroblasts into nude mice and 3-D epidermal equivalents revealed a positive role for AhR in skin regeneration, epidermal differentiation, and stem cell maintenance. Furthermore, lack of receptor expression in AhR-/- mice delayed morphogenesis and impaired hair regrowth with a phenotype closely correlating with a reduction in suprabasal bulge stem cells (α6low CD34+ ). Moreover, RNA-microarray and RT-qPCR analyses of fluorescence-activated cell sorting (FACS)-isolated bulge stem cells revealed that AhR depletion impaired transcriptional signatures typical of both epidermal progenitors and bulge stem cells but upregulated differentiation markers likely compromising their undifferentiated phenotype. Altogether, our findings support that AhR controls skin regeneration and homeostasis by ensuring epidermal stem cell identity and highlights this receptor as potential target for the treatment of cutaneous pathologies.

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms.

The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences.

Lack of the aryl hydrocarbon receptor accelerates aging in mice.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, largely known for its role in xenobiotic metabolism and detoxification as well as its crucial role as a regulator of inflammation. Here, we have compared a cohort wild-type and AhR-null mice along aging to study the relationship between this receptor and age-associated inflammation, termed as "inflammaging," both at a systemic and the CNS level. Our results show that AhR deficiency is associated with a premature aged phenotype, characterized by early inflammaging, as shown by an increase in plasma cytokines levels. The absence of AhR also promotes the appearance of brain aging anatomic features, such as the loss of the white matter integrity. In addition, AhR-/- mice present an earlier spatial memory impairment and an enhanced astrogliosis in the hippocampus when compared with their age-matched AhR+/+ controls. Importantly, we have found that AhR protein levels decrease with age in this brain structure, strongly suggesting a link between AhR and aging.-Bravo-Ferrer, I., Cuartero, M. I., Medina, V., Ahedo-Quero, D., Peña-Martínez, C., Pérez-Ruíz, A., Fernández-Valle, M. E., Hernández-Sánchez, C., Fernández-Salguero, P. M., Lizasoain, I., Moro, M. A. Lack of the aryl hydrocarbon receptor accelerates aging in mice.

Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch.

Genetic data indicate that abrogation of Notch-Rbpj or Wnt-ß-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of ß-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and ß-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal.

Alu retrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor.

Cell differentiation is a central process in development and in cancer growth and dissemination. OCT4 (POU5F1) and NANOG are essential for cell stemness and pluripotency; yet, the mechanisms that regulate their expression remain largely unknown. Repetitive elements account for almost half of the Human Genome; still, their role in gene regulation is poorly understood. Here, we show that the dioxin receptor (AHR) leads to differentiation of human carcinoma cells through the transcriptional upregulation of Alu retrotransposons, whose RNA transcripts can repress pluripotency genes. Despite the genome-wide presence of Alu elements, we provide evidences that those located at the NANOG and OCT4 promoters bind AHR, are transcribed by RNA polymerase-III and repress NANOG and OCT4 in differentiated cells. OCT4 and NANOG repression likely involves processing of Alu-derived transcripts through the miRNA machinery involving the Microprocessor and RISC. Consistently, stable AHR knockdown led to basal undifferentiation, impaired Alus transcription and blockade of OCT4 and NANOG repression. We suggest that transcripts produced from AHR-regulated Alu retrotransposons may control the expression of stemness genes OCT4 and NANOG during differentiation of carcinoma cells. The control of discrete Alu elements by specific transcription factors may have a dynamic role in genome regulation under physiological and diseased conditions.

A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-ß1 and aryl hydrocarbon receptor signaling.

Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor ß1 (TGF-ß1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-ß1 and AhR signaling in mouse mammary gland, through AhR+/+ and AhR-/- models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05µM HCB induced cell migration and TGF-ß1 signaling, whereas 5µM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5µM) enhanced α-smooth muscle actin expression and decreased TGF-ß receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR+/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR+/+ mice. Primary culture of mammary epithelial cells from AhR+/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5µM). Interestingly, AhR-/- mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-ß1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds.

L-kynurenine/aryl hydrocarbon receptor pathway mediates brain damage after experimental stroke.

BACKGROUND: Aryl hydrocarbon receptor (AhR) is a transcription factor that belongs to the basic helix-loop-helix PAS (Per-Arnt-Sim homology domain) family known to mediate the toxic and carcinogenic effects of xenobiotics. Interestingly, AhR is widely expressed in the central nervous system, but its physiological and pathological roles are still unclear. METHODS AND RESULTS: To define the role of AhR in stroke, we used middle cerebral artery occlusion in mice and oxygen-glucose deprivation in rat cortical neurons. The results presented here show that the ischemic insult increases total and nuclear AhR levels and AhR transcriptional activity in neurons in vivo and in vitro. We also show that AhR has a causal role in acute ischemic damage because pharmacological or genetic loss-of-function approaches result in neuroprotection. Inhibition of cAMP response element-binding protein-dependent signaling may participate in the deleterious actions of AhR. Finally, we have also found that L-kynurenine, a tryptophan metabolite with AhR agonistic properties, is an endogenous ligand that mediates AhR activation in the brain after middle cerebral artery occlusion. CONCLUSIONS: Our data demonstrate that an L-kynurenine/AhR pathway mediates acute brain damage after stroke and open new possibilities for the diagnosis and treatment of this pathology.

Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis.

BACKGROUND: The dioxin (AhR) receptor can have oncogenic or tumor suppressor activities depending on the phenotype of the target cell. We have shown that AhR knockdown promotes melanoma primary tumorigenesis and lung metastasis in the mouse and that human metastatic melanomas had reduced AhR levels with respect to benign nevi. METHODS: Mouse melanoma B16F10 cells were engineered by retroviral transduction to stably downregulate AhR expression, Aldh1a1 expression or both. They were characterized for Aldh1a1 activity, stem cell markers and migration and invasion in vitro. Their tumorigenicity in vivo was analyzed using xenografts and lung metastasis assays as well as in vivo imaging. RESULTS: Depletion of aldehyde dehydrogenase 1a1 (Aldh1a1) impairs the pro-tumorigenic and pro-metastatic advantage of melanoma cells lacking AhR expression (sh-AhR). Thus, Aldh1a1 knockdown in sh-AhR cells (sh-AhR + sh-Aldh1a1) diminished their migration and invasion potentials and blocked tumor growth and metastasis to the lungs in immunocompetent AhR+/+ recipient mice. However, Aldh1a1 downmodulation in AhR-expressing B16F10 cells did not significantly affect tumor growth in vivo. Aldh1a1 knockdown reduced the high levels of CD133(+)/CD29(+)/CD44(+) cells, melanosphere size and the expression of the pluripotency marker Sox2 in sh-AhR cells. Interestingly, Sox2 increased Aldh1a1 expression in sh-AhR but not in sh-AhR + sh-Aldh1a1 cells, suggesting that Aldh1a1 and Sox2 may be co-regulated in melanoma cells. In vivo imaging revealed that mice inoculated with AhR + Aldh1a1 knockdown cells had reduced tumor burden and enhanced survival than those receiving Aldh1a1-expressing sh-AhR cells. CONCLUSIONS: Aldh1a1 overactivation in an AhR-deficient background enhances melanoma progression. Since AhR may antagonize the protumoral effects of Aldh1a1, the AhR(low)-Aldh1a1(high) phenotype could be indicative of bad outcome in melanoma.

A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-ß) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-ß pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-ß-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-ß pathway, may predict lack of response to sorafenib in HCC patients.

Aryl hydrocarbon receptor contributes to the MEK/ERK-dependent maintenance of the immature state of human dendritic cells.

Dendritic cells (DCs) promote tolerance or immunity depending on their maturation state, which is enhanced or accelerated upon MEK-ERK signaling pathway inhibition. We have determined the contribution of MEK-ERK activation to the profile of gene expression of human immature monocyte-derived dendritic cells (MDDCs) and peripheral blood myeloid DCs. ERK inhibition altered the expression of genes that mediate Chemokine (C-C motif) ligand 19 (CCL19)-directed migration (CCR7) and low-density lipoprotein (LDL) binding (CD36, SCARB1, OLR1, CXCL16) by immature DCs. In addition, ERK upregulated CCL2 expression while impairing the expression of DC maturation markers (RUNX3, ITGB7, IDO1). MEK-ERK-regulated genes exhibited an overrepresentation of cognate sequences for the aryl hydrocarbon receptor (AhR) transcription factor, whose transcriptional and DNA-binding activities increased in MDDCs upon exposure to the MEK1/2 inhibitor U0126. Therefore, the MEK-ERK signaling pathway regulates antigen capture, lymph node homing, and acquisition of maturation-associated genes, and its contribution to the maintenance of the immature state of MDDCs and myeloid DCs is partly dependent on the activity of AhR. Since pharmacologic modulation of the MEK-ERK signaling pathway has been proposed as a potential therapeutic strategy for cancer, our findings indicate that ERK inhibitors might influence antitumor responses through regulation of critical DC effector functions.

Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor.

Skin is in daily contact with potentially harmful molecules from the environment such as cigarette smoke, automobile emissions, industrial soot and groundwater. Pregnane X receptor (PXR) is a transcription factor expressed in liver and intestine that is activated by xenobiotic chemicals including drugs and environmental pollutants. Topical application of the tumor initiator 7,12-dimethylbenz(a)anthracene (DMBA) enhances Pxr, Cyp1a1, Cyp1b1 and Cyp3a11, but not Ahr expression in the skin. Surprisingly, DMBA-induced Pxr upregulation is largely impaired in Langerin(+) cell-depleted skin, suggesting that DMBA mainly triggers Pxr in Langerin(+) cells. Furthermore, PXR deficiency protects from DNA damage in epidermal cells but to a lesser extent than aryl hydrocarbon receptor (AHR) deficiency. Interestingly, skin exposure to low doses of DMBA induces migration of PXR-deficient but not of wild-type and AHR-deficient Langerhans cells (LCs). PXR-humanized mice show a marked increase in DNA damage to epidermal cells after topical application of DMBA, demonstrating relevance of these findings in human tissue. This is the first report suggesting that carcinogens might trigger PXR in epidermal cells, particularly in LCs, thus leading to DNA damage. Further studies are required to better delineate the role of PXR in cutaneous carcinogenesis.

Dioxin receptor expression inhibits basal and transforming growth factor ß-induced epithelial-to-mesenchymal transition.

Recent studies have emphasized the role of the dioxin receptor (AhR) in maintaining cell morphology, adhesion, and migration. These novel AhR functions depend on the cell phenotype, and although AhR expression maintains mesenchymal fibroblasts migration, it inhibits keratinocytes motility. These observations prompted us to investigate whether AhR modulates the epithelial-to-mesenchymal transition (EMT). For this, we have used primary AhR(+/+) and AhR(-/-) keratinocytes and NMuMG cells engineered to knock down AhR levels (sh-AhR) or to express a constitutively active receptor (CA-AhR). Both AhR(-/-) keratinocytes and sh-AhR NMuMG cells had increased migration, reduced levels of epithelial markers E-cadherin and ß-catenin, and increased expression of mesenchymal markers Snail, Slug/Snai2, vimentin, fibronectin, and α-smooth muscle actin. Consistently, AhR(+/+) and CA-AhR NMuMG cells had reduced migration and enhanced expression of epithelial markers. AhR activation by the agonist FICZ (6-formylindolo[3,2-b]carbazole) inhibited NMuMG migration, whereas the antagonist α-naphthoflavone induced migration as did AhR knockdown. Exogenous TGFß exacerbated the promigratory mesenchymal phenotype in both AhR-expressing and AhR-depleted cells, although the effects on the latter were more pronounced. Rescuing AhR expression in sh-AhR cells reduced Snail and Slug/Snai2 levels and cell migration and restored E-cadherin levels. Interference of AhR in human HaCaT cells further supported its role in EMT. Interestingly, co-immunoprecipitation and immunofluorescence assays showed that AhR associates in common protein complexes with E-cadherin and ß-catenin, suggesting the implication of AhR in cell-cell adhesion. Thus, basal or TGFß-induced AhR down-modulation could be relevant in the acquisition of a motile EMT phenotype in both normal and transformed epithelial cells.

Dioxin receptor and SLUG transcription factors regulate the insulator activity of B1 SINE retrotransposons via an RNA polymerase switch.

Complex genomes utilize insulators and boundary elements to help define spatial and temporal gene expression patterns. We report that a genome-wide B1 SINE (Short Interspersed Nuclear Element) retrotransposon (B1-X35S) has potent intrinsic insulator activity in cultured cells and live animals. This insulation is mediated by binding of the transcription factors dioxin receptor (AHR) and SLUG (SNAI2) to consensus elements present in the SINE. Transcription of B1-X35S is required for insulation. While basal insulator activity is maintained by RNA polymerase (Pol) III transcription, AHR-induced insulation involves release of Pol III and engagement of Pol II transcription on the same strand. B1-X35S insulation is also associated with enrichment of heterochromatin marks H3K9me3 and H3K27me3 downstream of B1-X35S, an effect that varies with cell type. B1-X35S binds parylated CTCF and, consistent with a chromatin barrier activity, its positioning between two adjacent genes correlates with their differential expression in mouse tissues. Hence, B1 SINE retrotransposons represent genome-wide insulators activated by transcription factors that respond to developmental, oncogenic, or toxicological stimuli.

The Dioxin receptor modulates Caveolin-1 mobilization during directional migration: role of cholesterol.

BACKGROUND: Adhesion and migration are relevant physiological functions that must be regulated by the cell under both normal and pathological conditions. The dioxin receptor (AhR) has emerged as a transcription factor regulating both processes in mesenchymal, epithelial and endothelial cells. Indirect results suggest that AhR could cooperate not only with additional transcription factors but also with membrane-associated proteins to drive such processes. RESULTS: In this study, we have used immortalized and primary dermal fibroblasts from wild type (AhR+/+) and AhR-null (AhR-/-) mice to show that AhR modulates membrane distribution and mobilization of caveolin-1 (Cav-1) during directional cell migration. AhR co-immunoprecipitated with Cav-1 and a fraction of both proteins co-localized to detergent-resistant membrane microdomains (DRM). Consistent with a role of AhR in the process, AhR-/- cells had a significant reduction in Cav-1 in DRMs. Moreover, high cell density reduced AhR nuclear levels and moved Cav-1 from DRMs to the soluble membrane in AhR+/+ but not in AhR-/- cells. Tyrosine-14 phosphorylation had a complex role in the mechanism since its upregulation reduced Cav-1 in DRMs in both AhR+/+ and AhR-/-cells, despite the lower basal levels of Y14-Cav-1 in the null cells. Fluorescence recovery after photobleaching revealed that AhR knock-down blocked Cav-1 transport to the plasma membrane, a deficit possibly influencing its depleted levels in DRMs. Membrane distribution of Cav-1 in AhR-null fibroblasts correlated with higher levels of cholesterol and with disrupted membrane microdomains, whereas addition of exogenous cholesterol changed the Cav-1 distribution of AhR+/+ cells to the null phenotype. Consistently, higher cholesterol levels enhanced caveolae-dependent endocytosis in AhR-null cells. CONCLUSIONS: These results suggest that AhR modulates Cav-1 distribution in migrating cells through the control of cholesterol-enriched membrane microdomains. Our study also supports the likely possibility of membrane-related, transcription factor independent, functions of AhR.

The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis.

Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of ß1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.

Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene.

Aryl hydrocarbon receptor (Ahr) is a transcriptional factor involved in detoxification responses to pollutants and in intrinsic biological processes of multicellular organisms. We recently described that Vav3, an activator of Rho/Rac GTPases, is an Ahr transcriptional target in embryonic fibroblasts. These results prompted us to compare the Ahr(-/-) and Vav3(-/-) mouse phenotypes to investigate the implications of this functional interaction in vivo. Here, we show that Ahr is important for Vav3 expression in kidney, lung, heart, liver, and brainstem regions. This process is not affected by the administration of potent Ahr ligands such as benzo[a]pyrene. We also report that Ahr- and Vav3-deficient mice display hypertension, tachypnea, and sympathoexcitation. The Ahr gene deficiency also induces the GABAergic transmission defects present in the Vav3(-/-) ventrolateral medulla, a main cardiorespiratory brainstem center. However, Ahr(-/-) mice, unlike Vav3-deficient animals, display additional defects in fertility, perinatal growth, liver size and function, closure, spleen size, and peripheral lymphocytes. These results demonstrate that Vav3 is a bona fide Ahr target that is in charge of a limited subset of the developmental and physiological functions controlled by this transcriptional factor. Our data also reveal the presence of sympathoexcitation and new cardiorespiratory defects in Ahr(-/-) mice.

Aryl Hydrocarbon Receptor: From Homeostasis to Tumor Progression.

Transcription factor aryl hydrocarbon receptor (AHR) has emerged as one of the main regulators involved both in different homeostatic cell functions and tumor progression. Being a member of the family of basic-helix-loop-helix (bHLH) transcriptional regulators, this intracellular receptor has become a key member in differentiation, pluripotency, chromatin dynamics and cell reprogramming processes, with plenty of new targets identified in the last decade. Besides this role in tissue homeostasis, one enthralling feature of AHR is its capacity of acting as an oncogene or tumor suppressor depending on the specific organ, tissue and cell type. Together with its well-known modulation of cell adhesion and migration in a cell-type specific manner in epithelial-mesenchymal transition (EMT), this duality has also contributed to the arise of its clinical interest, highlighting a new potential as therapeutic tool, diagnosis and prognosis marker. Therefore, a deregulation of AHR-controlled pathways may have a causal role in contributing to physiological and homeostatic failures, tumor progression and dissemination. With that firmly in mind, this review will address the remarkable capability of AHR to exert a different function influenced by the phenotype of the target cell and its potential consequences.