Regulation of rat hepatocyte epidermal growth factor receptor by the liver tumor promoter ethinyl estradiol

We have previously demonstrated that the liver tumor promoter ethinyl estradiol (EE) greatly enhanced the DNA synthetic response of rat hepatocytes in primary culture to epidermal growth factor (EGF). This effect was associated with a 2-fold increase in surface EGF receptor number. In this report, we demonstrate that the increase in cell surface [125I]EGF binding caused by EE is time dependent, beginning at 8 h and reaching a plateau at 18 h. This increased EGF binding was accompanied by a comparable increase in the amount of total EGF receptor protein. In vivo, EE treatment also increased the number of EGF binding sites. EE treatment did not increase the rate of [35S]methionine incorporation into immunoprecipitated EGF receptor protein, nor did it appear to affect the steady-state levels of EGF receptor mRNA compared to that found in controls. However, EE treatment did cause an increase in the half-life of EGF receptor protein from 4.5±0.5 h in control hepatocytes to 10.4±1.8 h. Taken together, these results indicate that the EE-induced 2-fold increase in EGF receptor levels, which is associated with the potentiation of responsiveness to EGF, was brought about by stabilization of receptor protein.