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

✍ Scribed by Essam Enan; Debra Y. Dunlap; Fumio Matsumura

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 131 KB
• Volume: 12
• Category: Article
• ISSN: 1095-6670
• DOI: 10.1002/(sici)1099-0461(1998)12:5<263::aid-jbt2>3.0.co;2-j

✦ Synopsis

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.