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
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DOI：
10.1128/mcb.00206-09
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发表时间：
2009-07-01
影响因子：
5.3
通讯作者：
Hahn, Mark E.
中科院分区：
文献类型：
--
作者：
Karchner, Sibel I.;Jenny, Matthew J.;Hahn, Mark E.
芳烃受体（AHR）抑制因子（AHRR）抑制AHR介导的转录，并与人类生殖功能障碍和肿瘤发生有关。先前的研究已经描述了来自小鼠和鱼类的AHRR的抑制功能，但人类AHRR同源物（AHRR(715)）在体外似乎没有功能。在这里，我们报道了一个新的人类AHRR cDNA (AHRR Delta 8)，缺乏AHRR（715）的外显子8。AHRR δ 8是在人体组织和细胞系中表达的主要AHRR形式。AHRR δ 8有效地抑制ahr依赖性的交易激活，而AHRR（715）的活性要低得多。同样，AHRR Delta 8与AHR核转运子（ARNT）形成复合体，而AHRR（715）则没有。AHRR δ 8对AHR的抑制并未因ARNT或AHR共激活因子的过表达而减轻，这表明对这些辅助因子的竞争不是抑制的机制。AHR δ 8与AHR的相互作用较弱，但不抑制其核易位。在一项转录因子特异性调查中，AHRR δ 8不抑制核受体妊娠X受体或雌激素受体α，但抑制缺氧诱导因子（HIF）依赖的信号传导。AHR δ 8-Pro（185）和-Ala（185）变体与人类生殖疾病有关，两者都能够抑制AHR或HIF。总之，这些结果确定了AHRR Delta 8是人类AHRR的活性形式，并揭示了其作为抑制因子的功能和特异性的新方面。
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 Delta 8) that lacks exon 8 of AHRR(715). AHRR Delta 8 was the predominant AHRR form expressed in human tissues and cell lines. AHRR Delta 8 effectively repressed AHR-dependent transactivation, whereas AHRR(715) was much less active. Similarly, AHRR Delta 8, but not AHRR(715), formed a complex with AHR nuclear translocator (ARNT). Repression of AHR by AHRR Delta 8 was not relieved by overexpression of ARNT or AHR coactivators, suggesting that competition for these cofactors is not the mechanism of repression. AHRR Delta 8 interacted weakly with AHR but did not inhibit its nuclear translocation. In a survey of transcription factor specificity, AHRR Delta 8 did not repress the nuclear receptor pregnane X receptor or estrogen receptor alpha but did repress hypoxia-inducible factor (HIF)-dependent signaling. AHRR Delta 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 Delta 8 as the active form of human AHRR and reveal novel aspects of its function and specificity as a repressor.