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Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma


Transgenic mouse models have provided evidence that activation of the zinc-finger transcription factor GLI1 by Hedgehog (Hh)-signalling is a key step in the initiation of the tumorigenic programme leading to Basal Cell Carcinoma (BCC). However, the downstream events underlying Hh/GLI-induced BCC development are still obscure. Using in vitro model systems to analyse the effect of Hh/GLI-signalling in human keratinocytes, we identified a positive feedback mechanism involving the zinc finger transcription factors GLI1 and GLI2. Expression of GLI1 in human keratinocytes induced the transcriptional activator isoforms GLI2α and GLI2β. Both isoforms were also shown to be expressed at elevated levels in 21 BCCs compared to normal skin. Detailed time course experiments monitoring the transcriptional response of keratinocytes either to GLI1 or to GLI2 suggest that GLI1 is a direct target of GLI2, while activation of GLI2 by GLI1 is likely to be indirect. Furthermore, expression of either GLI2 or GLI1 led to an increase in DNA-synthesis in confluent human keratinocytes. Taken together, these results suggest an important role of the positive GLI1-GLI2 feedback loop in Hh-mediated epidermal cell proliferation.

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We thank Dr Ken Kinzler for the gift of GLI1 plasmid, Dr Paul Khavari for Sin-IP-GFP plasmid, Dr David Markovitz for providing human GLI2β expression plasmid, Dr Gary Nolan for the permission to use the Phoenix packaging cell line and Dr Norbert Fusenig for providing the HaCaT cell line. We are particularly grateful to Dr Harald Esterbauer for his advice and discussions about real-time PCR analysis and to Dr Emberger for histopathological analysis of BCC samples. This work was supported by FWF grant P14227-MOB (Austria), and the Medical Research Council (UK).

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Correspondence to Fritz Aberger.

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Regl, G., Neill, G., Eichberger, T. et al. Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma. Oncogene 21, 5529–5539 (2002).

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