Aberrant expression and regulation of hepatic epidermal growth factor receptor in a c-myc transgenic mouse model
✍ Scribed by Joseph T. Woitach; Elizabeth A. Conner; Peter J. Wirth; Snorri S. Thorgeirsson
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 209 KB
- Volume
- 64
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
In an attempt to elucidate the mechanism by which c-myc and transforming growth factor-a (TGF-a) cooperate in hepatocyte tumor development, we have analyzed signaling by the epidermal growth factor (EGF) receptor and the consequent regulation of receptor number in transgenic mice bearing the c-myc transgene under the control of the albumin enhancer/promoter. 125 I-EGF binding and Scatchard analysis indicated a single class of high affinity receptors with the total number of binding sites of 1.2 3 10 4 6 600 and 2.5 3 10 5 6 1000 sites/cell in the normal and c-myc hepatocytes in primary culture, respectively. After 72 h of EGF exposure in culture, the number of detectable EGF receptors on the cell surface of the c-myc hepatocytes was not reduced, whereas the number of EGF receptors on normal hepatocytes was reduced to 32% that of untreated hepatocytes. Nuclear run-on experiments done with nuclei isolated from intact livers demonstrated that transcription of the EGF receptor was 4.9-fold higher in c-myc mice. Increased levels of the transcriptional factor SP1 in the c-myc hepatocytes in vivo and in primary culture, suggest a mechanism for the increased transcription of the EGF receptor. c-myc also increases the expression of TGF-a; a consequent increase in tyrosine phosphorylation is also detected in vivo. Thus, the increased number of EGF receptors in c-myc expressing hepatocytes, even after prolonged exposure to EGF, or TGF-a in vivo, may allow greater triggering of the EGF receptor signaling cascade.