title: Aryl hydrocarbon receptor-dependent cell cycle arrest in isolated mouse oval cells.
abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which mediates toxic responses to environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Besides its well known role in induction of xenobiotic metabolizing enzymes, for instance CYP1A1, the AhR is also involved in tumor promotion in rodents although the underlying mechanisms are still poorly understood. Additionally, the AhR is known to regulate cellular proliferation, which might result in either inhibition or stimulation of proliferation depending on the cell-type studied. Potential targets in hepatocarcinogenesis are liver oval (stem/progenitor) cells. In the present work we analyzed the effect of TCDD on proliferation in oval cells derived from mouse liver. We show that TCDD inhibits proliferation in these cells. In line, the amount of G0/G1 cells increases in response to TCDD. We further show that the expression of cyclin D1 and cyclin A is decreased, while p27 is increased. As a result, the retinoblastoma protein is not phosphorylated thereby inducing G0/G1 arrest. Pharmacological inhibition of the AhR and knock-down of AhR expression by RNA interference decreased the inhibitory effect on cell cycle and protein expression, indicating that the AhR at least partially mediates cell cycle arrest.
authors.affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University, Obere Zahlbacherstr. 67, 55131 Mainz, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Faust
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kletting
authors.forename: Elke
authors.initials: E
authors.lastname: Ueberham
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014162:Transfection
chemical_list: D019925:Cyclin A; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D016160:Retinoblastoma Protein; C413374:p27 antigen; D019938:Cyclin D1
keywords: Aryl hydrocarbon receptor; Cell cycle; Mouse oval cells; TCDD