TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A

• Published in: Oncogene Vol. 27; no. 15; pp. 2198 - 2207
• Main Authors: Weiss, C, Faust, D, Schreck, I, Ruff, A, Farwerck, T, Melenberg, A, Schneider, S, Oesch-Bartlomowicz, B, Zatloukalová, J, Vondráček, J, Oesch, F, Dietrich, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2008; Nature Publishing; Nature Publishing Group
• Subjects: Adult Stem Cells - drug effects; Adult Stem Cells - physiology; Animals; Apoptosis; Aryl hydrocarbon nuclear translocator; Biological and medical sciences; Cancer; Cell Biology; Cell cycle; Cell cycle, cell proliferation; Cell physiology; Cell receptors; Cell structures and functions; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells, Cultured; Contact inhibition; Contact Inhibition - drug effects; Cyclin A; Cyclin A - metabolism; Cyclin A - physiology; Dimerization; Dioxins; DNA binding proteins; Ectopic expression; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Hepatocytes; Human Genetics; Hydrocarbons; Internal Medicine; Kinases; Liver; Liver - drug effects; Liver - metabolism; Medicine; Medicine & Public Health; Miscellaneous; Models, Biological; Molecular and cellular biology; Oncology; original-article; Physiological aspects; Polychlorinated Dibenzodioxins - pharmacology; Protein kinases; Proto-Oncogene Proteins c-jun - metabolism; Proto-Oncogene Proteins c-jun - physiology; Rats; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - metabolism; Receptors, Aryl Hydrocarbon - physiology; RNA, Small Interfering - pharmacology; Rodents; Signal transduction; TCDD; Toxicity; Transcription activation; Transcription factors; Tumorigenesis; Tumors; Germany; JunD; cell cycle control; contact inhibition; cyclin A; liver oval cells; aryl hydrocarbon receptor; Rat; Digestive system; Liver; Rodentia; Carcinogenesis; Ah receptor; Vertebrata; Regulation(control); Mammalia; Cyclin A; Cell cycle; Inhibition; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210859

The aryl hydrocarbon receptor (AhR) is a transcription factor involved in physiological processes, but also mediates most, if not all, toxic responses to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). Activation of the AhR by TCDD leads to its dimerization with aryl hydrocarbon nuclear translocator (ARNT) and transcriptional activation of several phase I and II metabolizing enzymes. However, this classical signalling pathway so far failed to explain the pleiotropic hazardous effects of TCDD, such as developmental toxicity and tumour promotion. Thus, there is an urgent need to define genetic programmes orchestrated by AhR to unravel its role in physiology and toxicology. Here we show that TCDD treatment of rat liver oval cells leads to induction of the transcription factor JunD, resulting in transcriptional upregulation of the proto-oncogene cyclin A which finally triggers a release from contact inhibition. Ectopic expression of cyclin A in confluent cultures overcomes G 1 arrest, indicating that increased cyclin A levels are indeed sufficient to bypass contact inhibition. Functional interference with AhR-, but not with ARNT, abolished TCDD-induced increase in JunD and cyclin A and prevented loss of contact inhibition. In summary, we have discovered a novel AhR-dependent and probably ARNT-independent signalling pathway involving JunD and cyclin A, which mediates TCDD-induced deregulation of cell cycle control.