HES-1, a Novel Target Gene for the Aryl Hydrocarbon Receptor

Known mainly for its role as a toxin sensor, the aryl hydrocarbon receptor (AhR) complex is also involved in homeostasis regulation and differentiation processes and activated by xenobiotic compounds like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hairy and Enhancer of Split homolog-1 (HES-1) is a key regulator not only in differentiation, but also in the cell cycle, and we show here that HES-1 is a new target gene for AhR regulation. HES-1 is up-regulated by TCDD both at protein and mRNA levels in T47D human mammary carcinoma cells. Actinomycin D experiments have shown that the AhR-mediated up-regulation of HES-1 mRNA is caused by transcriptional activation of the HES-1 gene, and we have identified a functional AhR response element (XRE) at -48/-42 in the upstream regulatory region of human HES-1. The HES-1 protein down-regulates expression of its own gene, and the HES element overlaps the XRE. Our data indicate that HES-1 and the AhR complex compete for binding to the composite HES/XRE element. Also, we have previously shown that HES-1 is down-regulated by the estrogen receptor ligand 17β-estradiol (E₂). Up-regulation of HES-1 expression is correlated with suppression of cell proliferation, and the E₂-mediated down-regulation of HES-1 therefore increases cell proliferation. It is known that TCDD exerts antiestrogenic action in breast tissue both in vivo and in vitro. Our observation that both the estrogen receptor and AhR signaling pathways regulate HES-1, but with opposing effects, suggests the existence of a new pathway by which AhR represses E₂-signaling.