Induction of the Ras activator Son of Sevenless 1 by environmental pollutants mediates their effects on cellular proliferation.
TCDD (2,3,7,8-tetrachlorodibenzodioxin), a highly persistent environmental pollutant and a human carcinogen, is the ligand with the highest affinity for the Aryl Hydrocarbon Receptor (AhR) that induces via the AhR, xenobiotic metabolizing enzyme genes as well as several other genes. This pollutant elicits a variety of systemic toxic effects, which include cancer promotion and diverse cellular alterations that modify cell cycle progression and cell proliferation. Large-scale studies have shown that the expression of Son of Sevenless 1 (SOS1), the main mediator of Ras activation, is one of the targets of dioxin in human cultured cells. In this study, we investigated the regulation of the previously uncharacterized SOS1 gene promoter by the AhR and its ligands in the human hepatocarcinoma cell line, HepG2. We found that several environmental pollutants (AhR ligands) induce SOS1 gene expression by increasing its transcription. Chromatin immunoprecipitation experiments demonstrated that the AhR binds directly and activates the SOS1 gene promoter. We also showed that dioxin treatment leads to an activated Ras-GTP state, to ERK activation and to accelerated cellular proliferation. All these effects were mediated by SOS1 induction as shown by knock down experiments. Our data indicate that dioxin-induced cellular proliferation is mediated, at least partially, by SOS1 induction. Remarkably, our studies also suggest that SOS1 induction leads to functional effects similar to those elicited by the well-characterized oncogenic Ras mutations.
INSERM UMR-S 747, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, 75006 Paris, France.
Stéphane
S
Pierre
Anne-Sophie
AS
Bats
Aline
A
Chevallier
Linh-Chi
LC
Bui
Ariane
A
Ambolet-Camoit
Michèle
M
Garlatti
Martine
M
Aggerbeck
Robert
R
Barouki
Xavier
X
Coumoul
D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D020837:SOS1 Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins