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Tumor Necrosis Factor Gene Expression Is Mediated by Protein Kinase C following Activation by Ionizing Radiation¹

Department of Radiation and Cellular Oncology, University of Chicago and Pritzker School of Medicine, Chicago, Illinois 60637 [D. E. H., S. V., E. H., R. R. W.]; Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute and Harvard Medicine School, Boston, Massachusetts 02115 [M. L. S., D. W. K.]; and Biological and Medical Research Division, Argonne National Laboratory, Argonne, Illinois 60439 and Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois 60637 [E. H.]

Tumor necrosis factor (TNF) production following X-irradiation has been implicated in the biological response to ionizing radiation. Protein kinase C (PKC) is suggested to participate in TNF transcriptional induction and X-ray-mediated gene expression. We therefore studied radiation-mediated TNF expression in HL-60 cells with diminished PKC activity produced by either pretreatment with protein kinase inhibitors or prolonged 12-O-tetradecanoylphorbol-13-acetate treatment. Both treatments resulted in attenuation of radiation-mediated TNF induction. Consistent with these results, we found no detectable induction of TNF expression following X-irradiation in the HL-60 variant deficient in PKC-mediated signal transduction. The rapid activation of PKC following -irradiation was established using an in vitro assay measuring phosphorylation of a PKC specific substrate. A 4.5-fold increase in PKC activity occurred 15 to 30 s following irradiation, which declined to baseline at 60 s. Two-dimensional gel electrophoresis of phosphoproteins extracted from irradiated cells demonstrated in vivo phosphorylation of the PKC specific substrate M_r 80,000 protein at 45 s following X-irradiation. These findings indicate that signal transduction via the PKC pathway is required for the induction of TNF gene expression by ionizing radiation.

¹ This work was supported by National Cancer Institute Grant CA41068, the Center for Radiation Therapy, the Chicago Tumor Institute, and in part by the United States Department of Energy, Office of Health and Environmental Research, under Contract W-31-109-ENG-38.

² To whom requests for reprints should be addressed, at Department of Radiation and Cell Oncology, University of Chicago, Pritzker School of Medicine, 5841 South Maryland Avenue, Chicago, IL 60637.

Received 3/ 8/91. Accepted 6/24/91.

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