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  • Original Paper
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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

Oncogene volume 19, pages 4011–4021 (2000)Cite this article

Abstract

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 of suitable animal model systems greatly facilitates the study of changes in the composition and activity of the AP-1 complex. Here, we have analysed the quantitative and qualitative changes of AP-1 at different stages of carcinogenesis in mouse skin cell lines, derived from tumours induced by chemical mutagens. The findings of this study suggest that elevated AP-1 DNA binding and transactivation activity characterize the carcinoma cell lines, most notably the highly malignant spindle carcinomas. In addition, increased amounts 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. Remarkably, high levels of phosphorylated ATF-2 protein were detected in malignant 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 present in tumour cells. Finally, our results indicate distinct functions for different AP-1 components in the promotion and progression of mouse skin tumours.

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Acknowledgements

We thank the members of the Gene Regulation Laboratory for the gifts of materials as well as for useful discussions and encouragement and particularly Dr D Plows for critical reading of the manuscript. We are grateful to Drs D Lallemand and Prof M Yaniv for providing the panel anti-Jun and anti-Fos specific antisera, to Dr E Black for kindly providing GST-c-Jun(1–79) plasmid and to Dr H Van Dam for the TRE Luc constructs. We also thank the following funding agencies for financial support: the European Union, the Cancer Research Campaign, the Greek Ministry of Research and Development.

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Authors and Affiliations

  1. Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens, 116 35, Greece

    Vassilis Zoumpourlis, Paraskevi Papassava & Alexandros Pintzas

  2. Onyx Pharmaceuticals, 3031 Research Drive, California, 94806, Richmond, CA, USA

    Spyros Linardopoulos

  3. CRC Beatson Laboratories, Garscube Estate, Switchback Rd., Glasgow, G61 1BD, UK

    David Gillespie

  4. UCSF Cancer Center, 2340 Sutter Street, San Francisco, 94143, California, CA, USA

    Allan Balmain

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  1. Vassilis Zoumpourlis
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Zoumpourlis, V., Papassava, P., Linardopoulos, S. et al. 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. Oncogene 19, 4011–4021 (2000). https://doi.org/10.1038/sj.onc.1203732

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