Hexachlorobenzene triggers AhR translocation to the nucleus, c-Src activation and EGFR transactivation in rat liver.
Hexachlorobenzene (HCB) is a widespread environmental pollutant. It has some properties that are typical for dioxin-like compounds that act mainly through the aryl hydrocarbon receptor (AhR) protein. Upon dioxin binding, the AhR translocates to the nucleus and modulates gene expression. At the same time, c-Src kinase frees from the AhR complex and thereby activates its own kinase activity, which acts as a trigger for the growth factor receptor signal transduction pathway. HCB is a weak agonist of the AhR, and the evidence that HCB toxicity is mediated via the AhR complex is limited and inconclusive. In the present study, female Wistar rats were administered HCB (1, 10 and 100mg/kg) for 30 days. Liver cytosolic AhR was translocated to the nucleus. The activity of liver microsomal c-Src increased at all assayed doses. HCB induced the association of the EGFR with c-Src and increased the phosphorylation of EGFR at tyrosine 845 (Tyr845), a known c-Src phosphorylation site. c-Src from WB-F344 cells treated with HCB exhibited increased protein levels and c-Src-pTyr416 phosphorylation than the control cells. Again HCB induced EGFR phosphorylation at Tyr845. Such an effect of HCB could not be detected when c-Src activity was blocked by PP2. All together, our data demonstrates that HCB may induce EGFR transactivation through an c-Src-dependent pathway.
Randi
Andrea Silvana
AS
Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to piso, Buenos Aires, CP 1121, Argentina.
Sanchez
Marcela Susana
MS
Alvarez
Laura
L
Cardozo
Julián
J
Pontillo
Carolina
C
Kleiman de Pisarev
Diana Leonor
DL
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D006581:Hexachlorobenzene / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D019061:src-Family Kinases
D004785:Environmental Pollutants; D005659:Fungicides, Industrial; D018336:Receptors, Aryl Hydrocarbon; D006581:Hexachlorobenzene; C483803:Egfr protein, rat; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases