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. 1979 Oct;76(10):5168–5172. doi: 10.1073/pnas.76.10.5168

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

Lih-Syng Lee 1,2, I Bernard Weinstein 1,2
PMCID: PMC413101  PMID: 315558

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°C or 22°C than at 4°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 receptor but by indirectly altering the conformation or inducing the clustering of EGF receptors. These and other membrane effects of this tumor promoter suggest that it is a valuable probe for elucidating complex aspects of membrane structure and function.

Keywords: phorbol esters, receptors, carcinogenesis, cell surface

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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