Aryl hydrocarbon receptor regulation of the cell cycle by chromatin modification

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DESCRIPTION (provided by applicant) Uncontrolled cell proliferation is the hallmark of cancer. Exposure to certain chemicals in the environment disrupts the regulation of cell proliferation, ultimately leading to carcinogenesis. The aryl hydrocarbon receptor (AhR) binds to numerous synthetic and natural compounds including environmental carcinogens such as some polyhalogenated aromatic hydrocarbons (e.g., dioxins, polychlorinated biphenyls) and polycyclic aromatic hydrocarbons (e.g., dimethylbenzanthracene). The AhR signaling pathway has been implicated in regulation and dysregulation of the cell cycle; however the molecular mechanisms of this regulatory role are unclear. Most of the previously described interactions have been established in asynchronously growing cell cultures. The overall hypothesis of the proposed research is that AhR is a cell cycle regulator and the role it plays, either as a promoter of cell cycle progression or an inducer of cell cycle arrest, depends on its ability to differentially associate with multi-protein complexes comprised of cell cycle regulators and chromatin modifiers. This research proposes to investigate the molecular mechanisms of chemically-induced carcinogenesis initiated through activation of the aryl hydrocarbon receptor signaling pathway in mammalian cell culture models amenable to synchronization by 1) determining protein-protein interactions with chromatin modifiers (histone deacetylases and DNA methyltransferases) and cell cycle regulators (E2F transcription factors, retinoblastoma [RB] tumor suppressors) at specific stages of the cell cycle, 2) assessing the targeting of cell cycle gene promoters by AhR-containing transcriptional complexes by chromatin immunoprecipitation (ChIP) experiments and genomic approaches including ChlP-on-chip and ChlP-cloning, and 3) determining how the regulatory role of AhR is disrupted by carcinogenic AhR ligands. The results from this research will provide a better understanding of chemically-induced carcinogenesis and gain insight into the molecular mechanisms for the varied responses in the cell cycle observed following exposure to environmental toxicants. Furthermore, the results will provide the basic research for developing therapeutic interventions to chemical-induced tumors and may predict cell cycle stages susceptible to cancer.