scholarly journals The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro185 and Ala185 Variants Repress both AHR and Hypoxia-Inducible Factor

2009 ◽  
Vol 29 (13) ◽  
pp. 3465-3477 ◽  
Author(s):  
Sibel I. Karchner ◽  
Matthew J. Jenny ◽  
Ann M. Tarrant ◽  
Brad R. Evans ◽  
Hyo Jin Kang ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Translocation ◽  
Active Form ◽  
Hypoxia Inducible Factor ◽  
Pregnane X Receptor ◽  
Estrogen Receptor Α ◽  
Aryl Hydrocarbon ◽  
Human Reproductive ◽  
Factor Specificity

ABSTRACT The aryl hydrocarbon receptor (AHR) repressor (AHRR) inhibits AHR-mediated transcription and has been associated with reproductive dysfunction and tumorigenesis in humans. Previous studies have characterized the repressor function of AHRRs from mice and fish, but the human AHRR ortholog (AHRR715) appeared to be nonfunctional in vitro. Here, we report a novel human AHRR cDNA (AHRRΔ8) that lacks exon 8 of AHRR715. AHRRΔ8 was the predominant AHRR form expressed in human tissues and cell lines. AHRRΔ8 effectively repressed AHR-dependent transactivation, whereas AHRR715 was much less active. Similarly, AHRRΔ8, but not AHRR715, formed a complex with AHR nuclear translocator (ARNT). Repression of AHR by AHRRΔ8 was not relieved by overexpression of ARNT or AHR coactivators, suggesting that competition for these cofactors is not the mechanism of repression. AHRRΔ8 interacted weakly with AHR but did not inhibit its nuclear translocation. In a survey of transcription factor specificity, AHRRΔ8 did not repress the nuclear receptor pregnane X receptor or estrogen receptor α but did repress hypoxia-inducible factor (HIF)-dependent signaling. AHRRΔ8-Pro185 and -Ala185 variants, which have been linked to human reproductive disorders, both were capable of repressing AHR or HIF. Together, these results identify AHRRΔ8 as the active form of human AHRR and reveal novel aspects of its function and specificity as a repressor.

scholarly journals Estrogen receptor-α and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells

2016 ◽  
Vol 437 ◽  
pp. 190-200 ◽  
Author(s):  
Ping Gong ◽  
Zeynep Madak-Erdogan ◽  
Jodi A. Flaws ◽  
David J. Shapiro ◽  
John A. Katzenellenbogen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Aryl Hydrocarbon Receptor ◽  
Estrogen Receptor Α ◽  
Target Cells ◽  
Aryl Hydrocarbon

scholarly journals Expression, Localization, and Activity of the Aryl Hydrocarbon Receptor in the Human Placenta

2018 ◽  
Vol 19 (12) ◽  
pp. 3762 ◽  
Author(s):  
Anaïs Wakx ◽  
Margaux Nedder ◽  
Céline Tomkiewicz-Raulet ◽  
Jessica Dalmasso ◽  
Audrey Chissey ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Human Placenta ◽  
Target Genes ◽  
Environmental Pollutants ◽  
Cell Fractionation ◽  
Protein Levels ◽  
Aryl Hydrocarbon ◽  
Epithelial Barriers ◽  
Expression And Activity

The human placenta is an organ between the blood of the mother and the fetus, which is essential for fetal development. It also plays a role as a selective barrier against environmental pollutants that may bypass epithelial barriers and reach the placenta, with implications for the outcome of pregnancy. The aryl hydrocarbon receptor (AhR) is one of the most important environmental-sensor transcription factors and mediates the metabolism of a wide variety of xenobiotics. Nevertheless, the identification of dietary and endogenous ligands of AhR suggest that it may also fulfil physiological functions with which pollutants may interfere. Placental AhR expression and activity is largely unknown. We established the cartography of AhR expression at transcript and protein levels, its cellular distribution, and its transcriptional activity toward the expression of its main target genes. We studied the profile of AhR expression and activity during different pregnancy periods, during trophoblasts differentiation in vitro, and in a trophoblast cell line. Using diverse methods, such as cell fractionation and immunofluorescence microscopy, we found a constitutive nuclear localization of AhR in every placental model, in the absence of any voluntarily-added exogenous activator. Our data suggest an intrinsic activation of AhR due to the presence of endogenous placental ligands.

scholarly journals Hepatitis B Virus X-Associated Protein 2 Is a Subunit of the Unliganded Aryl Hydrocarbon Receptor Core Complex and Exhibits Transcriptional Enhancer Activity

1998 ◽  
Vol 18 (2) ◽  
pp. 978-988 ◽  
Author(s):  
Brian K. Meyer ◽  
Marilyn G. Pray-Grant ◽  
John P. Vanden Heuvel ◽  
Gary H. Perdew
Keyword(s):  
Amino Acid ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Aryl Hydrocarbon Receptor ◽  
In Vitro Translation ◽  
Luciferase Reporter ◽  
Core Complex ◽  
Aryl Hydrocarbon ◽  
B Virus

ABSTRACT Prior to ligand activation, the unactivated aryl hydrocarbon receptor (AhR) exists in a heterotetrameric 9S core complex consisting of the AhR ligand-binding subunit, a dimer of hsp90, and an unknown subunit. Here we report the purification of an ∼38-kDa protein (p38) from COS-1 cell cytosol that is a member of this complex by coprecipitation with a FLAG-tagged AhR. Internal amino acid sequence information was obtained, and p38 was identified as the hepatitis B virus X-associated protein 2 (XAP2). The simian ortholog of XAP2 was cloned from a COS-1 cDNA library; it codes for a 330-amino-acid protein containing regions of homology to the immunophilins FKBP12 and FKBP52. A tetratricopeptide repeat (TPR) domain in the carboxy-terminal region of XAP2 was similar to the third and fourth TPR domains of human FKBP52 and the Saccharomyces cerevisiae transcriptional modulator SSN6, respectively. Polyclonal antibodies raised against XAP2 recognized p38 in the unliganded AhR complex in COS-1 and Hepa 1c1c7 cells. It was ubiquitously expressed in murine tissues at the protein and mRNA levels. It was not required for the assembly of an AhR-hsp90 complex in vitro. Additionally, XAP2 did not directly associate with hsp90 upon in vitro translation, but was present in a 9S form when cotranslated in vitro with murine AhR. XAP2 enhanced the ability of endogenous murine and human AhR complexes to activate a dioxin-responsive element–luciferase reporter twofold, following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells.

scholarly journals Sequence and functional characterization of hypoxia-inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish, Fundulus heteroclitus

2017 ◽  
Vol 312 (3) ◽  
pp. R412-R425 ◽  
Author(s):  
Ian K. Townley ◽  
Sibel I. Karchner ◽  
Elena Skripnikova ◽  
Thomas E. Wiese ◽  
Mark E. Hahn ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Fundulus Heteroclitus ◽  
Phylogenetic Analyses ◽  
Functional Characterization ◽  
Hypoxia Inducible Factor ◽  
Estuarine Fish ◽  
Low Oxygen ◽  
Aryl Hydrocarbon ◽  
Transactivation Domains

The hypoxia-inducible factor (HIF) family of transcription factors plays central roles in the development, physiology, pathology, and environmental adaptation of animals. Because many aquatic habitats are characterized by episodes of low dissolved oxygen, fish represent ideal models to study the roles of HIF in the response to aquatic hypoxia. The estuarine fish Fundulus heteroclitus is found in habitats prone to hypoxia. It responds to low oxygen via behavioral, physiological, and molecular changes, and one member of the HIF family, HIF2α, has been previously described. Herein, cDNA sequencing, phylogenetic analyses, and genomic approaches were used to determine other members of the HIFα family from F. heteroclitus and their relationships to HIFα subunits from other vertebrates. In vitro and cellular approaches demonstrated that full-length forms of HIF1α, HIF2α, and HIF3α independently formed complexes with the β-subunit, aryl hydrocarbon receptor nuclear translocator, to bind to hypoxia response elements and activate reporter gene expression. Quantitative PCR showed that HIFα mRNA abundance varied among organs of normoxic fish in an isoform-specific fashion. Analysis of the F. heteroclitus genome revealed a locus encoding a second HIF2α—HIF2αb—a predicted protein lacking oxygen sensing and transactivation domains. Finally, sequence analyses demonstrated polymorphism in the coding sequence of each F. heteroclitus HIFα subunit, suggesting that genetic variation in these transcription factors may play a role in the variation in hypoxia responses among individuals or populations.

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