TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38-MAPK-dependent pathway.
The aryl hydrocarbon receptor (AhR) has a fundamental role during postnatal liver development and is essential for mediating dioxin toxicity. However, the genetic programs mediating, both, the toxic and physiological effects downstream of the transcription factor AhR are in major parts unknown. We have identified the proto-oncogene c-jun as a novel target gene of AhR. Induction of c-jun depends on activation of p38-mitogen-activated protein kinase (MAPK) by an AhR-dependent mechanism. None of the kinases that are known to phosphorylate p38-MAPK is activated by AhR. Neither the dephosphorylation rate of p38-MAPK is reduced. Furthermore, increased p38-MAPK phosphorylation in response to dioxins does not require ongoing transcription. These findings establish activating 'cross-talk' with MAPK signaling as a novel principle of AhR action, which is apparently independent of the AhR's function as a DNA-binding transcriptional activator.
Weiss
Carsten
C
Institute of Toxicology, University of Mainz, 55131 Mainz, Germany. weissca@uni-mainz.de
Faust
Dagmar
D
Dürk
Heike
H
Kolluri
Siva Kumar
SK
Pelzer
Anke
A
Schneider
Sandra
S
Dietrich
Cornelia
C
Oesch
Franz
F
Göttlicher
Martin
M
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017931:DNA Primers; C000715470:MAS1 protein, human; D000072317:Polychlorinated Dibenzodioxins; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D048051:p38 Mitogen-Activated Protein Kinases