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J. Biol. Chem., Vol. 277, Issue 9, 6949-6959, March 1, 2002
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From the Biology Department, Woods Hole Oceanographic Institution,
Woods Hole, Massachusetts 02543
The effects of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related
compounds occur via the aryl hydrocarbon receptor (AHR), a member of
the basic helix-loop-helix-Per-ARNT-Sim homology (bHLH-PAS) protein
superfamily. A single AHR gene has been identified in mammals, whereas many fish species, including the Atlantic killifish (Fundulus heteroclitus) possess two distinct
AHR genes (AHR1 and a novel form,
AHR2). A mouse bHLH-PAS protein closely related to AHR and
designated AHR repressor (AHRR) is induced by 3-methylcholanthrene and
represses the transcriptional activity of the AHR. To determine whether
AHRR is the mammalian ortholog of fish AHR2 and to investigate the
mechanisms by which AHRR regulates AHR function, we cloned an AHRR
ortholog in F. heteroclitus with high sequence identity to
the mouse and human AHRRs. Killifish AHRR encodes a 680-residue protein
with a predicted molecular mass of 75.2 kDa. We show that in
vitro expressed AHRR proteins from human, mouse, and killifish all fail to bind [3H]TCDD or
[3H] The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF443441 and AF443442.
Regulatory Interactions among Three Members of the Vertebrate
Aryl Hydrocarbon Receptor Family: AHR Repressor, AHR1, and
AHR2*
, and
-naphthoflavone. In transient transfection
experiments using a luciferase reporter gene under control of AHR
response elements, killifish AHRR inhibited the
TCDD-dependent transactivation function of both AHR1 and
AHR2. AHRR mRNA is widely expressed in killifish tissues and is
inducible by TCDD or polychlorinated biphenyls, but its expression is
not altered in a population of fish exhibiting genetic resistance to
these compounds. The F. heteroclitus AHRR promoter contains
three putative AHR response elements. Both AHR1 and AHR2 activated
transcription of luciferase driven by the AHRR promoter, and AHRR could
repress its own promoter. Thus, AHRR is an evolutionarily conserved,
TCDD-inducible repressor of AHR1 and AHR2 function. Phylogenetic
analysis shows that AHRR, AHR1, and AHR2
are distinct genes, members of an AHR gene family; these three
vertebrate AHR-like genes descended from a single invertebrate AHR.
*
This work was supported in part by National Institutes of
Health Grants R01 ES06272 (to M. E. H.) and F32 ES05800 (to
W. H. P.) and the Superfund Basic Research Program Grant P42 ES07381 at Boston University. This is contribution 10562 from the Woods Hole
Oceanographic Institution.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Biology Dept., Kenyon College, Gambier, OH 43022.
§
To whom correspondence should be addressed: Biology Dept., MS 32, Woods Hole Oceanographic Institution, Woods Hole, MA 02543-1049. Tel.:
508-289-3242; Fax: 508-457-2134; E-mail: mhahn@whoi.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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