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

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 (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.

HIF-mediated metabolic switching in bladder outlet obstruction mitigates the relaxing effect of mitochondrial inhibition

“…17 Here we found that Arnt2 (HIF-2b) and Arntl2, both of which are capable of forming transactivation competent heterodimers with HIF-1a, 16,18 are upregulated at the mRNA level in outlet obstruction already at 10 days. Ahrr, which encodes a protein that represses HIF-1a, 19 was reduced. Together, these changes may facilitate HIF-1 activation independently of HIF-1a protein accumulation in bladder outlet obstruction.…”

“…18 The dioxin receptor repressor Ahrr has finally been reported to inhibit HIFdependent transcription. 19 Together, these possibilities add several layers of complexity to HIF activation that have not been addressed in bladder outlet obstruction.…”

Molecular phylogenies and evolutionary behavior of AhR (aryl hydrocarbon receptor) pathway genes in aquatic animals: Implications for the toxicology mechanism of some persistent organic pollutants (POPs)

“…Repression occurs through competition between AhR and AHRR for binding to AHREs (Mimura et al, 1999) as well as through additional mechanisms that do not involve competition for ARNT and are independent of AHRE binding by AHRR (Evans et al, 2008). Recently, studies of Karchner et al (2009) revealed that AHRR48 (a novel human AHRR cDNA) is the active form of human AHRR and reveal novel aspects of its function and specificity as a repressor. Without doubt, many issues have not been answered; so, targeted knockdown of one or both AHRR proteins by application of morpholino oligonucleotides can be used to further characterize the AHRRs and to elucidate their potential roles in development and in the developmental toxicity of chemicals such as TCDD in the future.…”

Alternative Negative Feedback Control in the Aryl Hydrocarbon Receptor Signaling Pathway

“…AHRR is structurally similar to AHR, but it does not bind ligand and it lacks a transcriptional activation domain. Overexpression studies strongly support AHRR as a ligand-induced repressor of AHR [11,12]. It was originally proposed that AHRR bound and sequestered ARNT resulting in the quenching of AHR transactivation [11].…”

“…It was originally proposed that AHRR bound and sequestered ARNT resulting in the quenching of AHR transactivation [11]. However, AHRR was recently reported to interact directly with AHR and overexpression of ARNT failed to rescue AHRR-dependent repression of AHR [12]. Repression of CYP1 activity in human skin fibroblast was not correlated with AHRR expression levels [13].…”