Ionizing Radiation-Mediated Protein Kinase C Activation and Gene Expression

Abstract

Ionizing radiation-induced neoplastic transformation is postulated to occur as a consequence of an initial common event followed by a rare second event. Genes encoding transcription factors are expressed immediately after x-ray exposure in the absence of de novo protein synthesis. c-jun, c-fos and Egr-1 are expressed following irradiation of human normal tissue cells and tumor cell lines. Radiation-mediated expression of these immediate early genes is attenuated by protein kinase inhibitors and abrogated when protein kinase C (PKC) is down regulated or when PKC-mediated signal transduction is deficient. PKC is the target for the tumor promoter phorbol esters. This enzyme has been implicated to play a role in neoplastic transformation and in cellular proliferation following mitogenic stimulation. PKC is also, activated rapidly following ionizing radiation exposure. Radiation-mediated PKC activation and immediate early gene induction may represent initial common events which are then followed by rare presumably mutational processes which result in neoplastic transformation. The potential importance of this finding is demonstrated by the recent report that PKC inhibitors partially suppress neoplastic transformation following x-irradiation. The production of growth factors and cytokines within irradiated tissues may also contribute to tumor promotion or progression. This discussion addresses the molecular processes that occur within a cell following x-irradiation and their potential role in neoplastic transformation.