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

Abstract

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 Ϫ48/Ϫ42 in the upstream regulatory region of human HES-1. The HES-1 protein downregulates 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 downregulated by the estrogen receptor ligand 17␤-estradiol (E 2 ). Up-regulation of HES-1 expression is correlated with suppression of cell proliferation, and the E 2 -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 E 2 -signaling.The balance between cell proliferation and cell differentiation affects cell fate; therefore, the proteins involved in these key biological processes must be tightly regulated. Many of the transcription factors involved constitute an intricate network of proteins belonging to the basic helix-loophelix (bHLH) superfamily of DNA binding transcription factors. The Hairy and Enhancer of Split homolog-1 (HES-1) is known to play a role in neuronal differentiation (Kageyama and Nakanishi, 1997) and belongs to the family of bHLH transcriptional repressors related to the Drosophila melanogaster Hairy and Enhancer of Split proteins. HES-1 also inhibits cell proliferation in neuronal cells (Castella et al

Dysregulation of Notch and ERα signaling in AhR−/−male mice

“…One of the main Notch effector genes is Hairy and Enhancer of Split homolog 1 (HES1). We have shown that HES1 is an AhR target gene (15). This result indicates that AhR could regulate spermatogenesis by controlling HES1 expression.…”

The Aryl Hydrocarbon Receptor Contributes to the Proliferation of Human Medulloblastoma Cells

“…Hes1 promotes proliferation of GNPs and subsequently is involved in the pathogenesis of MB (Solecki et al, 2001;Fogarty et al, 2005). In addition, Hes1 has been established as an AhR target gene (Thomsen et al, 2004). Therefore, we investigated whether Hes1 expression was altered after the knockdown of AhR in DAOY cells.…”

“…For example, AhR overexpression in neuroblastoma cells resulted in a neuronal phenotype as a result of augmented differentiation (Akahoshi et al, 2006). AhR has been reported to control the expression of genes that influence growth and differentiation, which are dysregulated in cancer, suggesting that AhR may be involved in tumor development and progression (Thomsen et al, 2004;Yang et al, 2005).…”

“…AhR activation up-regulates xenobiotic-metabolizing enzymes, which have been linked to cancer development through altered metabolic clearing of carcinogenic xenobiotics that may also bioactivate procarcinogens . In addition, AhR modulates the expression of growth-associated genes such as c-Myc, Hes1, p21 cip1 , and p27 kip1 (Thomsen et al, 2004;Yang et al, 2005).…”

“…For example, the Notch signaling pathway, which is up-regulated in MB tissue, promotes proliferation and inhibits cell cycle exit of GNPs, through the induction of the basic helix-loop-helix transcription factor Hes1 (Solecki et al, 2001;Fogarty et al, 2005). Of interest, Hes1 has been reported as an AhR target gene (Thomsen et al, 2004). In the inner EGL, several genes that act as intrinsic promoters of GNP cell cycle exit, including p27 kip1 and p21 cip1 , which have both been suspected in MB pathogenesis, have been identified (Argenti et al, 2005).…”