Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Haarmann‐Stemmann, Thomas; Bothe, Hanno; Kohli, Amitabh; Sydlik, Ulrich; Abel, Josef; Fritsche, Ellen

doi:10.1124/dmd.107.016253

Cited by 73 publications

(71 citation statements)

References 42 publications

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“…However, in the few studies to examine the function of the hAHRR protein, it has not always been clear which form was being investigated (21,29,30,71). The substantial difference in repressor activity between the two forms described here (Fig.…”

Section: Discussionmentioning

confidence: 89%

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

Karchner

Jenny

Tarrant

et al. 2009

Molecular and Cellular Biology

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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 (AHRR 715 ) appeared to be nonfunctional in vitro. Here, we report a novel human AHRR cDNA (AHRR⌬8) that lacks exon 8 of AHRR 715 . AHRR⌬8 was the predominant AHRR form expressed in human tissues and cell lines. AHRR⌬8 effectively repressed AHR-dependent transactivation, whereas AHRR 715 was much less active. Similarly, AHRR⌬8, but not AHRR 715 , formed a complex with AHR nuclear translocator (ARNT). Repression of AHR by AHRR⌬8 was not relieved by overexpression of ARNT or AHR coactivators, suggesting that competition for these cofactors is not the mechanism of repression. AHRR⌬8 interacted weakly with AHR but did not inhibit its nuclear translocation. In a survey of transcription factor specificity, AHRR⌬8 did not repress the nuclear receptor pregnane X receptor or estrogen receptor ␣ but did repress hypoxia-inducible factor (HIF)-dependent signaling. AHRR⌬8-Pro 185 and -Ala 185 variants, which have been linked to human reproductive disorders, both were capable of repressing AHR or HIF. Together, these results identify AHRR⌬8 as the active form of human AHRR and reveal novel aspects of its function and specificity as a repressor.

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Section: Discussionmentioning

confidence: 89%

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

Karchner

Jenny

Tarrant

et al. 2009

Molecular and Cellular Biology

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“…In addition, HDAC inhibition is implemented in the aryl hydrocarbon receptor (AhR)-mediated induction of CYP1A1 and CYP1A2 [130], and CYP3A4 induction by rifampicin [131]. Next to genes coding for xenobiotic biotransformation enzymes, HDACi also stimulate the transcription of other liverspecific genes, including phosphoenol-pyruvate carboxykinase [57], HCFX [11], apolipoprotein CIII [11], glucose-6-phosphatase [57] and glutamine synthetase [11].…”

Section: Effect Of Hdac and Dnmt Inhibition On Liverspecific Gene Expmentioning

confidence: 98%

Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation

Snykers

Henkens

Rop

et al. 2009

Journal of Hepatology

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Controlling both growth and differentiation of stem cells and their differentiated somatic progeny is a challenge in numerous fields, from preclinical drug development to clinical therapy. Recently, new insights into the underlying molecular mechanisms have unveiled key regulatory roles of epigenetic marks driving cellular pluripotency, differentiation and self-renewal/proliferation. Indeed, the transcription of genes, governing cell-fate decisions during development and maintenance of a cell's differentiated status in adult life, critically depends on the chromatin accessibility of transcription factors to genomic regulatory and coding regions. In this review, we discuss the epigenetic control of (liver-specific) gene-transcription and the intricate interplay between chromatin modulation, including histone (de)acetylation and DNA (de)methylation, and liver-enriched transcription factors. Special attention is paid to their role in directing hepatic differentiation of primary hepatocytes and stem cells in vitro.

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“…Additionally, the regulation of AhR signaling cascade might be different in unresponsive cells like eelB or human fibroblasts. In the case of human fibroblasts, poor CYP1A1 induction had been attributed to high levels of AhR repressor protein (AhRR) (Haarmann-Stemmann et al 2007). However, this idea was rejected recently (Tigges et al 2013), leaving open the possibility that repression might occur at the level of CYP1A mRNA translation (Tigges et al 2013).…”

Section: Neurospheres Of Eelbmentioning

confidence: 99%

Development of a cell line from the American eel brain expressing endothelial cell properties

Bloch

Walsh

et al. 2015

In Vitro Cell.Dev.Biol.-Animal

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A cell line (eelB) was developed from the outgrowth of adherent cells from brain explants of the American eel, Anguilla rostrata (Lesueur). EelB cells have been grown routinely in L-15 with 10% fetal bovine serum (FBS), undergone over 100 passages, and cryopreserved successfully. The cells from late-passage cultures (>45) were polygonal, formed capillary-like structures (CLS) on Matrigel, and stained immunocytochemically for von Willebrand factor (vWF) and for three tight junction proteins, zonula occludens-1 (ZO-1), claudin 3, and claudin 5. These results suggest that eelB is an endothelial cell line, one of the few from fish and the first from the brain. Despite this, eelB did not respond to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with the induction of CYP1A protein. The cells from early-passage cultures (<20) had more varied shapes and did not form CLS on Matrigel. Only cells from early-passage cultures formed in suspension three-dimensional aggregates that had some cells expressing alkaline phosphatase and nestin. These cells are thought to be neural stem cells and the aggregates neurospheres. The emergence of endothelial-like cells upon the continued subcultivation of cells from early-passage cultures that had neural stem cells has been described previously for mammals, but this is a first for teleosts. Remarkably, cells from all passage levels were stained strongly for senescence-associated β-galactosidase (SA β-Gal) activity.

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Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Cited by 73 publications

References 42 publications

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

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

Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation

Development of a cell line from the American eel brain expressing endothelial cell properties

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Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Cited by 73 publications

References 42 publications

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

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

Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation

Development of a cell line from the American eel brain expressing endothelial cell properties

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Product

Resources

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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

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