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The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells

Oncogene volume 23, pages 1263–1274 (2004)Cite this article

Abstract

In stratified epidermis, activation of the Hh/Gli signal transduction pathway has been implicated in the control of cell proliferation and tumorigenesis. The zinc-finger transcription factor Gli2 has been identified as critical mediator of the Hh signal at the distal end of the pathway, but the molecular mechanisms by which Gli2 regulates cell proliferation or induces epidermal malignancies such as basal cell carcinoma are still unclear. Here, we provide evidence for a role of human GLI2 in antagonizing contact inhibition and epidermal differentiation. We show by gene expression profiling that activation of the GLI2 oncogene in human keratinocytes activates the transcription of a number of genes involved in cell cycle progression such as E2F1, CCND1, CDC2 and CDC45L, while it represses genes associated with epidermal differentiation. Analysis of the proliferative effect of GLI2 revealed that GLI2 is able to induce G1–S phase progression in contact-inhibited keratinocytes. Detailed time-course experiments identified E2F1 as early transcriptional target of GLI2. Further, we show that GLI2 expression in human keratinocytes results in a marked downregulation of epidermal differentiation markers. The data suggest a role for GLI2 in Hh-induced epidermal neoplasia by opposing epithelial cell cycle arrest signals and epidermal differentiation.

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Acknowledgements

We are grateful to Sabine Siller for excellent technical assistance, to Drs Harald Esterbauer and Alexandra Kaser for critical reading of the manuscript and to Prof. Helmut Hintner for supply with tumour and normal skin material. This work was supported by FWF project P14227 (Austria), the University of Salzburg Schwerpunkt ‘Biomedizin und Gesundheit’, the Stiftungs- und Foerderungsgesellschaft of the University of Salzburg and by an EMBO short-term fellowship to TE.

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  1. Institute of Genetics, University of Salzburg, Hellbrunner Strasse 34, Salzburg, A-5020, Austria

    Gerhard Regl, Maria Kasper, Harald Schnidar, Thomas Eichberger, Anna-Maria Frischauf & Fritz Aberger

  2. Center for Cutaneaous Research, Barts and The London Queen Mary's School of Medicine & Dentistry, University of London, UK

    Graham W Neill, Mohammed S Ikram & Mike P Philpott

  3. Experimental Medicine, AstraZeneca R & D Charnwood, Leicestershire, UK

    Anthony G Quinn

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  1. Gerhard Regl
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Correspondence to Fritz Aberger.

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Regl, G., Kasper, M., Schnidar, H. et al. The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells. Oncogene 23, 1263–1274 (2004). https://doi.org/10.1038/sj.onc.1207240

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