PMID: 315558Oct 1, 1979Paper

Mechanism of tumor promoter inhibition of cellular binding of epidermal growth factor

Proceedings of the National Academy of Sciences of the United States of America
L S Lee, I B Weinstein

Abstract

In previous studies we demonstrated that the tumor-promoting agent 12-O-tetradecanoyl phorbol 13-acetate (TPA) and related macrocyclic diterpenes are potent inhibitors of the binding of epidermal growth factor (EGF) to its cell surface receptors in HeLa cells. The present study explores the specificity and mechanism of this effect. We have found that the same effect is observed in various cell types derived from mice, rats, or humans. In HeLa cells TPA inhibits the initial binding of EGF and also accelerates the loss of previously bound EGF from cells. The released EGF is recovered largely intact in the medium, indicating that TPA does not induce increased proteolysis or increased cellular internalization and degradation of EGF. The TPA effect on EGF receptors is mediated by a highly temperature-dependent process because TPA inhibition of EGF binding, and TPA-induced release of prebound EGF, are much greater at 37 degrees C or 22 degrees C than at 4 degrees C. A curious feature is that when cells are grown in TPA for one or more days they escape or become refractory to TPA inhibition of EGF binding. Taken together, these results suggest that TPA inhibits EGF binding not by binding directly to the "active site" of the EGF recept...Continue Reading

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