High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model

Analysis of the functions of AP-1 transcription factor in cellular systems has shown its key role as a mediator of oncogenic signals. The employment o f suitable animal model systems greatly facilitates the study of changes in the composition and activity of the AP-1 complex. Here, we have analysed t he quantitative and qualitative changes of AP-1 at different stages of carc inogenesis in mouse skin cell lines, derived from tumours induced by chemic al mutagens. The findings of this study suggest that elevated AP-1 DNA bind ing and transactivation activity characterize the carcinoma cell lines, mos t notably the highly malignant spindle carcinomas. In addition, increased a mounts and post-translational modifications of c-Jun, Fra-1, Fra-2 and ATF- 2 proteins account for a high percentage of the increased AP-1 activity. Re markably, high levels of phosphorylated ATF-2 protein were detected in mali gnant cell lines, indicating a novel role of ATF-2 in tumour progression. c -Jun and ATF-2 proteins are phosphorylated by highly active JNK kinases pre sent in tumour cells. Finally, our results indicate distinct functions for different AP-1 components in the promotion and progression of mouse skin tu mours.