TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A.
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.
Weiss
C
C
Institute of Toxicology, Johannes Gutenberg-University, Mainz, Germany.
Faust
D
D
Schreck
I
I
Ruff
A
A
Farwerck
T
T
Melenberg
A
A
Schneider
S
S
Oesch-Bartlomowicz
B
B
Zatloukalová
J
J
Vondrácek
J
J
Oesch
F
F
Dietrich
C
C
D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D003260:Contact Inhibition / Q000187:drug effects*; D019925:Cyclin A / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
D019925:Cyclin A; D000072317:Polychlorinated Dibenzodioxins; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon