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ActivatingSmoothened mutations in sporadic basal-cell carcinoma
- Jingwu Xie1,2,
- Maximilien Murone3,
- Shiuh-Ming Luoh3,
- Anne Ryan4,
- Qimin Gu5,
- Chaohui Zhang3,
- Jeannette M. Bonifas1,2,
- Ching-Wan Lam7,
- Mary Hynes6,
- Audrey Goddard5,
- Arnon Rosenthal6,
- Ervin H Epstein Jr1,2 &
- …
- Frederic J. de Sauvage3
Naturevolume 391, pages90–92 (1998)Cite this article
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Abstract
Basal-cell carcinomas (BCCs) are the commonest human cancer1. Insight into their genesis came from identification of mutations in the PATCHED gene(PTCH) in patients with the basal-cell nevus syndrome, a hereditary disease characterized by multiple BCCs and by developmental abnormalities2,3,4,5,6,7. The binding of Sonic hedgehog (SHH) to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of Smoothened (SMO), a seven-span transmembrane protein8,9. According to this model, the inhibition of SMO signalling is relieved following mutational inactivation of PTCH in basal-cell nevus syndrome. We report here the identification of activating somatic missense mutations in theSMO gene itself in sporadic BCCs from three patients. Mutant SMO, unlike wild type, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture. Furthermore, skin abnormalities similar to BCCs developed in transgenic murine skin overexpressing mutant SMO. These findings support the role of SMO as a signalling component of the SHH–receptor complex and provide direct evidence that mutated SMO can function as an oncogene in BCCs.
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Acknowledgements
We thank D. Sherman and V. Bhagwandin for technical help, J. Ramirez for histology, K. Hagler for immunohistochemistry, E. Nelson for help with the animals, the Genentech DNA synthesis group, C. Hoffman and W. Anstine for preparing the figures, E. Fuchs for the K5 promoter, J.Gitscher for facilitating our collaboration and F. McCormick and M. Scott for advice and discussions. J.X. was the recipient of a Neutrogena fellowship of the Dermatology Foundation. Research in San Francisco was supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases.
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Authors and Affiliations
Department of Dermatology, San Francisco General Hospital, 1001 Potrero Street, Rm 269, Bldg 100
Jingwu Xie, Jeannette M. Bonifas & Ervin H Epstein Jr
University of California, San Francisco, 94110, California, USA
Jingwu Xie, Jeannette M. Bonifas & Ervin H Epstein Jr
Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA
Maximilien Murone, Shiuh-Ming Luoh, Chaohui Zhang & Frederic J. de Sauvage
Department of Pathology Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA
Anne Ryan
Department of Molecular Biology Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA
Qimin Gu & Audrey Goddard
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA
Mary Hynes & Arnon Rosenthal
Department of Chemical Pathology, Prince of Wales Hospital, Shatin, Hong Kong
Ching-Wan Lam
- Jingwu Xie
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- Maximilien Murone
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- Shiuh-Ming Luoh
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- Anne Ryan
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- Qimin Gu
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- Chaohui Zhang
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- Jeannette M. Bonifas
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- Ching-Wan Lam
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- Mary Hynes
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- Audrey Goddard
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- Arnon Rosenthal
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- Ervin H Epstein Jr
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- Frederic J. de Sauvage
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Correspondence toErvin H Epstein Jr orFrederic J. de Sauvage.
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Xie, J., Murone, M., Luoh, SM.et al. ActivatingSmoothened mutations in sporadic basal-cell carcinoma.Nature391, 90–92 (1998). https://doi.org/10.1038/34201
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