Use of c-Src and c-Fos knockout mice for the studies on the role of c-Src kinase signaling in the expression of toxicity of TCDD.
Previously, we reported that several of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were not fully expressed in c-src -/- and -/+ mice (1). In the current study, we studied the basic molecular mechanism of their differential responses. First, we could show that chemical inhibition of c-src kinase could produce practically the same phenomenon of reduced toxicity of TCDD in wild-type mice cotreated with geldanamycin, a specific chemical inhibitor known to suppress c-src kinase. Second, we established that the level of the Ah receptor associated with c-src kinase (2) is indeed low in c-src deficient mice as well as geldanamycin-treated mice. We could show, at the same time, that the effect of c-src deficiency on the toxicity of TCDD is very selective; that is, despite the reduction of many of its toxic signs, the enlargement of liver, induction of cytochrome P450, and other drug-metabolizing enzymes took place normally in those c-src-deficient mice. Apparently, induction of these detoxification enzymes are independent of c-src-mediated pathway. Based on the known signaling pathways of c-src, we tested c-fos-deficient mice and found that some of the c-src-dependant toxic signs of TCDD such as thymic atrophy and decrease in adipose tissue weight were also reduced in c-fos-deficient mice, indicating that these two toxic effects are likely to be mediated through both c-src and c-fos. However, other TCDD responses noticeable in c-fos-deficient mice; downregulation of receptors for epidermal growth factor (EGF), tumor necrosis factor (TNF alpha), and retinoic acid; and up-regulation of the T3 receptor. These findings clearly show that c-fos mediates only a part of c-src signaling pathway in transducing these specific toxic actions of TCDD as mediated by c-fos.
Department of Environmental Toxicology, University of California, Davis 95616, USA.
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Enan
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Dunlap
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D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones; D000081247:CSK Tyrosine-Protein Kinase; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D016762:Genes, fos / Q000235:genetics*; D016391:Genes, src / Q000235:genetics*; D047029:Lactams, Macrocyclic; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011809:Quinones / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D018909:src Homology Domains / Q000187:drug effects; D019061:src-Family Kinases
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D000072317:Polychlorinated Dibenzodioxins; D011809:Quinones; D018336:Receptors, Aryl Hydrocarbon; D017978:Receptors, Growth Factor; D011988:Receptors, Thyroid Hormone; D003577:Cytochrome P-450 Enzyme System; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C001277:geldanamycin