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Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours

Nature volume 389, pages 876–881 (1997)Cite this article

An Erratum to this article was published on 04 December 1997

Abstract

Sporadic basal cell carcinoma (BCC) is the most common type of malignant cancer in fair-skinned adults. Familial BCCs and a fraction of sporadic BCCs have lost the function of Patched (Ptc), a Sonic hedgehog (Shh) receptor1,2,3 that acts negatively on this signalling pathway. Overexpression of Shh can induce BCCs in mice4. Here we show that ectopic expression of the zinc-finger transcription factor Gli1 in the embryonic frog epidermis results in the development of tumours that express endogenous Gli1. We also show that Shh and the Gli genes are normally expressed in hair follicles, and that human sporadic BCCs consistently express Gli1 but not Shh or Gli3. Because Gli1, but not Gli3, acts as a target and mediator of Shh signalling5, our results suggest that expression of Gli1 in basal cells induces BCC formation. Moreover, loss of Ptc or overexpression of Shh cannot be the sole causes of Gli1 induction and sporadic BCC formation, as they do not occur consistently. Thus any mutations leading to the expression of Gli1 in basal cells are predicted to induce BCC formation.

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Figure 1: Ectopic expression of Gli1 in frog embryos leads to the formation of epidermal tumours.
Figure 2: Gene expression in basal cell carcinomas and cell lines.
Figure 3: Expression of endogenous Gli1 and Shh in Gli1-induced tadpole tumours.

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Acknowledgements

We thank E. Ziff, G. Fishell, R. Brewster and C. Loomis for comments on the manuscript; K. Schulman for advice on selected tumour samples; L. Bernardo for cryostat sectioning; P.Censullo for help with tissue culture; E. Belloni and L. C. Tsui for a human Shh cDNA; E. Cordero for secretarial assistance; and J. Weider for help and advice with imaging. P.H. was a recipient of an Anne and Irving Holtzman fellowship in dermatopathology. This work was supported by a start-up grant from the Skirball Institute, a Basil O'Connor Award from the March of Dimes, and a fellowship from The Pew Scholars program in the biomedical sciences to A.R.A.

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Authors and Affiliations

  1. Developmental Genetics Program and Department of Cell Biology, The Skirball Institute, 540 First Avenue, New York, 10016, New York, USA

    N. Dahmane, J. Lee & A. Ruiz i Altaba

  2. Department of Dermatology, New York University Medical Center, 540 First Avenue, New York, 10016, New York, USA

    P. Robins & P. Heller

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  1. N. Dahmane
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Correspondence to A. Ruiz i Altaba.

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Dahmane, N., Lee, J., Robins, P. et al. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389, 876–881 (1997). https://doi.org/10.1038/39918

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