ABERRANT EXPRESSION AND REGULATION OF HEPATIC EPIDERMAL GROWTH-FACTORRECEPTOR IN A C-MYC TRANSGENIC MOUSE MODEL

In an attempt to elucidate the mechanism by which c-myc and transformi ng growth factor-alpha (TGF-alpha) cooperate in hepatocyte tumor devel opment, we have analyzed signaling by the epidermal growth factor (EGF ) receptor and the consequent regulation of receptor number in transge nic mice bearing the c-myc transgene under the control of the albumin enhancer/promoter. I-125-EGF binding and Scatchard analysis indicated a single class of high affinity receptors with the total number of bin ding sites of 1.2 x 10(4) +/- 600 and 2.5 x 10(5) +/- 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 re ceptors 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 transcriptio n of the EGF receptor was 4.9-fold higher in c-myc mice. Increased lev els of the transcriptional factor SP1 in the c-myc hepatocytes in vivo and in primary culture, suggest a mechanism for the increased transcr iption of the EGF receptor. c-myc also increases the expression of TGF -alpha; a consequent increase in tyrosine phosphorylation is also dete cted in vivo. Thus, the increased number of EGF receptors in c-myc exp ressing hepatocytes, even after prolonged exposure to EGF, or TGF-alph a in vivo, may allow greater triggering of the EGF receptor signaling cascade. (C) 1997 Wiley-Liss Inc.