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Activating Smoothened mutations in sporadic basal-cell carcinoma

Author

Listed:
  • Jingwu Xie

    (San Francisco General Hospital
    University of California)

  • Maximilien Murone

    (Genentech Inc.)

  • Shiuh-Ming Luoh

    (Genentech Inc.)

  • Anne Ryan

    (Department of Pathology Genentech Inc.)

  • Qimin Gu

    (Department of Molecular Biology Genentech Inc.)

  • Chaohui Zhang

    (Genentech Inc.)

  • Jeannette M. Bonifas

    (San Francisco General Hospital
    University of California)

  • Ching-Wan Lam

    (Prince of Wales Hospital)

  • Mary Hynes

    (Genentech Inc.)

  • Audrey Goddard

    (Department of Molecular Biology Genentech Inc.)

  • Arnon Rosenthal

    (Genentech Inc.)

  • Ervin H Epstein

    (San Francisco General Hospital
    University of California)

  • Frederic J. de Sauvage

    (Genentech Inc.)

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 the SMO 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.

Suggested Citation

  • Jingwu Xie & Maximilien Murone & Shiuh-Ming Luoh & Anne Ryan & Qimin Gu & Chaohui Zhang & Jeannette M. Bonifas & Ching-Wan Lam & Mary Hynes & Audrey Goddard & Arnon Rosenthal & Ervin H Epstein & Frede, 1998. "Activating Smoothened mutations in sporadic basal-cell carcinoma," Nature, Nature, vol. 391(6662), pages 90-92, January.
    • Handle: RePEc:nat:nature:v:391:y:1998:i:6662:d:10.1038_34201
    DOI: 10.1038/34201
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    Cited by:

    1. Brittany N. Vandenberg & Marian F. Laughery & Cameron Cordero & Dalton Plummer & Debra Mitchell & Jordan Kreyenhagen & Fatimah Albaqshi & Alexander J. Brown & Piotr A. Mieczkowski & John J. Wyrick & S, 2023. "Contributions of replicative and translesion DNA polymerases to mutagenic bypass of canonical and atypical UV photoproducts," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Xiaoliang Liu & Patricia T. Yam & Sabrina Schlienger & Eva Cai & Jingyi Zhang & Wei-Ju Chen & Oscar Torres Gutierrez & Vanesa Jimenez Amilburu & Vasanth Ramamurthy & Alice Y. Ting & Tess C. Branon & M, 2024. "Numb positively regulates Hedgehog signaling at the ciliary pocket," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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