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Abstract
The discovery that the oxygen-regulated transcription factor HIF-1 alpha and the dioxin
receptor AhR share the common heterodimerization partner ARNT (HIF-1 beta) raised
the question whether a cross-talk between oxygen and dioxin signal transduction pathways
exists. To answer this question we investigated an ARNT-deficient mutant cell line
(Hepa1C4), which has lost its capability of responding to dioxin. The results demonstrate
that the presence of ARNT is indispensable for hypoxia-inducible HIF-1 DNA binding
as well as for oxygen-regulated reporter gene activity mediated by the EPO 3' hypoxia
response element (HRE). Hypoxic induction of the vascular endothelial growth factor
(VEGF) gene, however, was only partially abrogated in Hepa1C4 cells, suggesting that
HIF-1-independent oxygen signaling pathways might exist. We further studied HIF-1
and AhR/ARNT DNA binding activity as well as the regulation of oxygen- and xenobiotic-responsive
genes by treating mouse Hepa1 hepatoma cells with hypoxia and/or the dioxin analogue
ICZ. Hypoxia-inducible VEGF expression was found to be independent of ICZ-treatment,
whereas ICZ-inducible cytochrome P-450IA1 expression was slightly reduced by hypoxic
treatment of the cells. Interestingly, the enhancer function of a xenobiotic response
element (XRE) linked to a reporter gene was induced by hypoxia, but expression of
a HRE-containing reporter gene was not affected by ICZ treatment.