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Evidence for autocrine/paracrine growth stimulation by transforming growth factor‐α during the process of skin tumor promotion
Author(s) -
Imamoto Akira,
Beltrán Linda M.,
Digiovanni John
Publication year - 1991
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.2940040109
Subject(s) - epidermal growth factor , biology , autocrine signalling , protein kinase c , paracrine signalling , growth factor , epidermis (zoology) , 12 o tetradecanoylphorbol 13 acetate , cytosol , tgf alpha , stimulation , tumor promotion , receptor , microbiology and biotechnology , biochemistry , endocrinology , medicine , kinase , carcinogenesis , phorbol ester , gene , anatomy , enzyme
A single topical application of 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA) to mouse skin decreased 125 I‐labeled epidermal growth factor (EGF) binding in epidermal membrane preparations within 1 h while 1,8‐dihydroxy‐3‐methyl‐9‐anthrone (chrysarobin) gradually reduced binding with maximum inhibition at 15 h. Subsequently, 125 I‐EGF binding increased to ∼ 200% of control in epidermal membrane preparations from both TPA‐ and chrysarobin‐treated mice. A single application of TPA but not chrysarobin resulted in a rapid translocation of protein kinase C (PKC) to the membrane; however, treatment with both promoters ultimately led to a time‐dependent loss of PKC activity in both membrane and cytosol fractions. The initial inhibition of 125 I‐EGF binding was sustained for at least 24 h after single and multiple treatments with both promoting agents. Acid washing restored EGF binding to control levels in membrane preparations obtained 24 h after a single application, whereas acid washing of membrane preparations obtained 24 h after a second application of TPA or chrysarobin increased binding (2.5‐fold and 1.5‐fold that of the control, respectively). The presence of increased amounts of ligands for the EGF receptor in tumor promoter‐treated epidermis was initially confirmed in 125 I‐EGF binding competition experiments using NRK‐49F cells. A single topical application of TPA or chrysarobin induced elevated levels of transforming growth factor‐α (TGF‐α) mRNA at 6 h or 15–24 h, respectively. Elevated levels of a TGF‐α precursor (21 kDa) were subsequently observed in cytosol and membrane preparations after single and multiple applications of TPA or chrysarobin. These results suggest that repeated topical application of tumor promoters may lead to sustained loss of a negative‐feedback mechanism involving phosphorylation at Thr‐654 of the EGF receptor by PKC. The concomitant elevation of ligands, such as TGF‐α, may provide a mechanism for sustained cell proliferation essential for skin tumor promotion.