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Molecular and Cellular Biology, July 2009, p. 3465-3477, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.00206-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown} ,{dagger}

Sibel I. Karchner,1 Matthew J. Jenny,1 Ann M. Tarrant,1 Brad R. Evans,1,2 Hyo Jin Kang,3 Insoo Bae,3 David H. Sherr,4 and Mark E. Hahn1*

Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543,1 Biology Department, Boston University, Boston, Massachusetts 02215,2 Department of Oncology, Georgetown University Medical Center, Washington, DC 20007,3 Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 021184

Received 16 February 2009/ Accepted 10 April 2009

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 (AHRR{Delta}8) that lacks exon 8 of AHRR715. AHRR{Delta}8 was the predominant AHRR form expressed in human tissues and cell lines. AHRR{Delta}8 effectively repressed AHR-dependent transactivation, whereas AHRR715 was much less active. Similarly, AHRR{Delta}8, but not AHRR715, 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-Pro185 and -Ala185 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.

* Corresponding author. Mailing address: Biology Department, MS#32, Woods Hole Oceanographic Institution Woods Hole, MA 02543. Phone: (508) 289-3242. Fax: (508) 457-2134. E-mail: mhahn{at}whoi.edu

{triangledown} Published ahead of print on 20 April 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2009, p. 3465-3477, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.00206-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Jenny, M. J., Karchner, S. I., Franks, D. G., Woodin, B. R., Stegeman, J. J., Hahn, M. E. (2009). Distinct Roles of Two Zebrafish AHR Repressors (AHRRa and AHRRb) in Embryonic Development and Regulating the Response to 2,3,7,8-Tetrachlorodibenzo-p-dioxin. Toxicol Sci 110: 426-441 [Abstract] [Full Text]  


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