Abstract
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic, teratogenic, and carcinogenic effects. TCDD is a ligand for the aromatic hydrocarbon receptor (AHR), a ligand-activated transcription factor believed to be the primary mediator of these effects. Activation of the AHR by TCDD also elicits a variety of effects on cell cycle progression, ranging from proliferation to arrest. In this report, we have characterized further the role of the activated AHR in cell cycle regulation. In human mammary carcinoma MCF-7 and mouse hepatoma Hepa-1 cells, TCDD treatment decreased the number of cells in S phase and caused the accumulation of cells in G(1). In Hepa-1 cells, this effect correlated with the transcriptional repression of several E2F-regulated genes required for S phase progression. AHR-mediated gene repression was dependent on its interaction with retinoblastoma protein but was independent of its transactivation function because AHR mutants lacking DNA binding or transactivation domains repressed E2F-dependent expression as effectively as wild type AHR. Overexpression of p300 suppressed retinoblastoma protein-dependent gene repression, and this effect was reversed by TCDD. Chromatin immunoprecipitation assays showed that TCDD treatment caused the recruitment of AHR to E2F-dependent promoters and the concurrent displacement of p300. These results delineate a novel mechanism whereby the AHR, a known transcriptional activator, also mediates gene repression by pathways involving combinatorial interactions at E2F-responsive promoters, leading to the repression of E2F-dependent, S phase-specific genes. The AHR seems to act as an environmental checkpoint that senses exposure to environmental toxicants and responds by signaling cell cycle inhibition.
Highlights
Includes many halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons and is a model for the outcome of exposure to these compounds as well as coplanar polychlorinated biphenyls
Additional observations indicated that aromatic hydrocarbon receptor (AHR) activation by TCDD treatment in serum-starved, RBpositive cells resulted in a significant reduction in both RB phosphorylation and cyclin D1 expression [63]
We show that AHR activation by TCDD inhibits cell cycle progression, accumulating cells in G1, and represses the transcription of E2F-dependent genes through interaction with RB
Summary
Includes many halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons and is a model for the outcome of exposure to these compounds as well as coplanar polychlorinated biphenyls. Gene transactivation mediated by the AHR represents an adaptive response required for the detoxification of foreign compounds This effect does not adequately explain the range of toxic outcomes resulting from TCDD exposure in different systems, regarding gene repression effects as seen for transforming growth factor-2 [37, 38], fibrinogen ␥ chain and plastin mRNAs [39], cyclin A [40], and others [41]. Global gene expression studies indicate that the AHR participates in the direct and indirect modulation of the transcriptional program [41], at least in part by associating with additional transcription factors [42,43,44] and coactivators or corepressors [45,46,47] Such associations may be partially responsible for the myriad effects of the ligand-activated AHR in the regulation of proliferation, apoptosis, differentiation, and signal transduction pathways [41]. Our results help elucidate the complex role played by AHR signaling during the cell cycle and delineate a novel role for the AHR, a known transactivator, in gene repression
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