The c-jun proto-oncogene has been implicated in the regulation of cellular growth and differentiation. This gene is activated as an immediate early cellular response to stimulation with serum, growth factors and phorbol esters. Studies from this laboratory have demonstrated that c-jun gene expression is induced following treatment of mammalian cells with DNA- damaging agents. In particular, ionizing radiation increases c-jun mRNA levels by a transcriptional mechanism in a dose- and time-dependent manner. These findings have indicated that activation of c-jun expression is a cellular response to DNA damage. The c-jun gene codes for a transcription factor that binds to the phorbol ester responsive DNA element. The affinity of Jun for DNA binding is related to dimerization with other leucine zipper transcription factors. Our results demonstrate that ionizing radiation also induces the expression of genes with homology to c-jun, including jun-B and c-fos. Furthermore, while ionizing radiation-induced signaling pathways that control c-jun gene transcription remain unclear, preliminary studies indicate that protein kinase C activation is required for these effects. The proposed studies will determine the basis for the activation of these signaling events and the significance of inducing genes coding for transcription factors in the potential regulation of a specific genetic response.
The specific aims of this proposal are: 1) to determine the effects of ionizing radiation on expression of the jun/fos gene families; 2) to study the transcriptional and posttranscriptional regulation of c-jun expression induced by ionizing radiation; 3) to study the involvement of protein kinases in signaling pathways activated by ionizing radiation-induced DNA damage; and 4) to determine whether c-jun gene expression is associated with specific cellular responses to the genotoxic effects of ionizing radiation. Cancer induction is one of the most important late effects after exposure to ionizing radiation. Although epidemiology studies have demonstrated a relationship between exposure to external radiation of ingested radionuclides and carcinogenesis, less is known about the molecular processes that occur during the latent period. The proposed studies will examine the hypothesis that distinct molecular mechanisms are involved in the transcriptional and posttranscriptional regulation c-jun/c-fos gene expression by ionizing radiation. Thus it is hoped that these studies will provide certain insights into the regulation of early response gene expression by radiation and will lead to a greater understanding of the molecular mechanisms involved in the mutagenic and carcinogenic as well as the cell killing effects of ionizing radiation.
