It is the goal of this study to understand the regulation and expression of protein kinase C, a major receptor for tumor promoters which has been implicated in the process of hormone-mediated cellular mitogenesis as well as tumor promotion. Having demonstrated that the epidermal growth factor receptor is a biological target of protein kinase C action, our initial aim is to use this system following treatment with tumor promoters to determine the number and nature of the different activation states of C kinase. Once the level of active enzyme required to induce a biological response is determined, we will explore the role of C kinase in the action of different growth enhancers on nontransformed cells. The differences in protein kinase C activity in transformed relative to nontransformed cells will be analyzed, as well as the causes of C kinase inactivation. Finally, we plan to prepare antibody directed against protein kinase C as an aid in achieving these goals. An understanding of the factors which regulate the activation of protein kinase C should provide valuable information regarding the mechanisms of mitogenic stimulation, hormonal regulation, and the onset of tumor promotion.

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National Cancer Institute (NCI)
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Physiological Chemistry Study Section (PC)
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Massachusetts Institute of Technology
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Friedman, B; Fujiki, H; Rosner, M R (1990) Regulation of the epidermal growth factor receptor by growth-modulating agents: effects of staurosporine, a protein kinase inhibitor. Cancer Res 50:533-8
Hicks, K; Friedman, B; Rosner, M R (1989) Basic fibroblast-like growth factor is present in the conditioned medium of simian sarcoma virus transformed NRK cells. Biochem Biophys Res Commun 164:1323-30
Hicks, K; Friedman, B; Rosner, M R (1989) Basic and acidic fibroblast growth factors modulate the epidermal growth factor receptor by a protein kinase C-independent pathway. Biochem Biophys Res Commun 164:796-803
Wattenberg, E V; McNeil, P L; Fujiki, H et al. (1989) Palytoxin down-modulates the epidermal growth factor receptor through a sodium-dependent pathway. J Biol Chem 264:213-9
Friedman, B A; van Amsterdam, J; Fujiki, H et al. (1989) Phosphorylation at threonine-654 is not required for negative regulation of the epidermal growth factor receptor by non-phorbol tumor promoters. Proc Natl Acad Sci U S A 86:812-6
Takishima, K; Friedman, B; Fujiki, H et al. (1988) Thapsigargin, a novel promoter, phosphorylates the epidermal growth factor receptor at threonine 669. Biochem Biophys Res Commun 157:740-6
Friedman, B A; Rosner, M R (1987) Growth factors modify the epidermal growth factor receptor through multiple pathways. J Cell Biochem 34:1-11
McCaffrey, P G; Rosner, M R (1987) Growth state-dependent regulation of protein kinase C in normal and transformed murine cells. Cancer Res 47:1081-6
McCaffrey, P G; Rosner, M R; Kikkawa, U et al. (1987) Characterization of protein kinase C from normal and transformed cultured murine fibroblasts. Biochem Biophys Res Commun 146:140-6
Wattenberg, E V; Fujiki, H; Rosner, M R (1987) Heterologous regulation of the epidermal growth factor receptor by palytoxin, a non-12-O-tetradecanoylphorbol-13-acetate-type tumor promoter. Cancer Res 47:4618-22

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