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Vol. 56, Issue 6, 1127-1137, December 1999
Department of Biochemistry and Molecular Biology, Medical
University of South Carolina, Charleston, South Carolina
The aryl hydrocarbon nuclear translocator (ARNT) protein
functions as a transcription factor after dimerization with other basic
helix-loop-helix proteins. Thus, dimerization of ARNT within one
pathway may limit the availability of this protein to others. To
investigate this issue, aryl hydrocarbon receptor (AHR)-mediated signaling was investigated in mouse (Hepa-1), rat (H4IIE), and human
(HepG2) hepatoma cell lines undergoing physiologically induced hypoxia
(<1% O2). Basal levels of ARNT protein were not affected by hypoxia in any cell line, and ARNT remained exclusively nuclear. Furthermore, quantitative Western blotting revealed that the
concentration of ARNT sequestered during hypoxia represented a small
fraction of the total ARNT protein pool (12 and 15% in Hepa-1 and H4
cells, respectively). When the AHR-mediated signaling pathway was
activated during hypoxia by
2,3,7,8-tetrachlorodibenzo-p-dioxin, the induction of
P4501A1 protein was reduced by 55% without changes in the level of mRNA in Hepa-1 cells, whereas the levels of induction of both P4501A1 protein and CYP1A1 mRNA were reduced by >80% in
the H4 cell line. Importantly, gel mobility shift analysis and Western blotting showed that the same level of AHR/ARNT complexes could be
detected in cells treated with
2,3,7,8-tetrachlorodibenzo-p-dioxin during hypoxia and
normoxia. These data suggest that the effects of hypoxia on
AHR-mediated gene regulation occur distal to the formation of AHR/ARNT
complexes and imply that functional interference between hypoxia and
AHR-mediated signaling does not occur through competition for ARNT protein.
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