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Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis

Oncogene volume 21, pages 4266–4276 (2002)Cite this article

Abstract

The two calgranulins S100A8 and S100A9 were found to be differentially expressed at sites of acute and chronic inflammation. Here we have employed the phorbol ester-induced multistage skin carcinogenesis protocol in mice to determine the expression of both genes in inflamed skin and in skin tumors. We show that expression is coordinately induced by the phorbol ester TPA in epithelial cells as well as infiltrating leukocytes. By comparing S100A8 and S100A9 mRNA levels in wild type and c-Fos deficient mice (c-fos−/−) we found that expression is negatively regulated by c-Fos/AP-1. Glucocorticoids, which exhibit potent anti-inflammatory and anti-tumor promoting activities repressed TPA-mediated S100A8 and S100A9 induction in wild type, but not in c-fos−/− mice, thus identifying both genes as the first examples of AP-1 target genes whose repression of TPA-induced transcription by glucocorticoids depends on c-Fos. Finally, we show that enhanced expression is not restricted to the initial TPA-induced inflammatory response but is observed at all stages of skin carcinogenesis. These data identify S100A8 and S100A9 as novel, tumor-associated genes and may point to an as yet unrecognized function of both genes in the development of epithelial skin tumors.

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Acknowledgements

We thank Dr G Fürstenberger (DKFZ) for providing murine skin tumors and Drs H Friesel, B Sorg and E Hecker (DKFZ) for TPA. We thank Dr D Meyer (DKFZ) for help with PCNA staining. Dr F Amelung (DKFZ) is gratefully acknowledged for his advices concerning histopathology. This work was supported in part, by Grants from the Training and Mobility of Research (CT96-0044) and BioMed-2 (CT BMH4-98-3505) Programs of the European Community.

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Author notes

  1. Ute Breitenbach

    Present address: Beiersdorf AG, Hamburg, Germany

  2. Jan Peter Tuckermann

    Present address: Division of Molecular Biology of the Cell I, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany

Authors and Affiliations

  1. Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany

    Christoffer Gebhardt, Bernd Thilo Dittrich, Karl Hartmut Richter & Peter Angel

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Correspondence to Peter Angel.

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Gebhardt, C., Breitenbach, U., Tuckermann, J. et al. Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis. Oncogene 21, 4266–4276 (2002). https://doi.org/10.1038/sj.onc.1205521

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