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Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

Author

Listed:
  • Jussi Taipale

    (Department of Molecular Biology and Genetics)

  • James K. Chen

    (Department of Molecular Biology and Genetics)

  • Michael K. Cooper

    (Department of Molecular Biology and Genetics
    The Johns Hopkins University School of Medicine)

  • Baolin Wang

    (Department of Molecular Biology and Genetics)

  • Randall K. Mann

    (Department of Molecular Biology and Genetics)

  • Ljiljana Milenkovic

    (Howard Hughes Medical Institute, Stanford University School of Medicine)

  • Matthew P. Scott

    (Howard Hughes Medical Institute, Stanford University School of Medicine)

  • Philip A. Beachy

    (Department of Molecular Biology and Genetics)

Abstract

Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway1,2. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response3,4, is a potential ‘mechanism-based’ therapeutic agent for treatment of these tumours. We show that cyclopamine or synthetic derivatives with improved potency block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.

Suggested Citation

  • Jussi Taipale & James K. Chen & Michael K. Cooper & Baolin Wang & Randall K. Mann & Ljiljana Milenkovic & Matthew P. Scott & Philip A. Beachy, 2000. "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine," Nature, Nature, vol. 406(6799), pages 1005-1009, August.
    • Handle: RePEc:nat:nature:v:406:y:2000:i:6799:d:10.1038_35023008
    DOI: 10.1038/35023008
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    Cited by:

    1. Wenlong Hou & Hao Lin & Yanru Wu & Chuang Li & Jiajun Chen & Xiao-Yu Liu & Yong Qin, 2024. "Divergent and gram-scale syntheses of (–)-veratramine and (–)-cyclopamine," Nature Communications, Nature, vol. 15(1), pages 1-6, December.
    2. Alessandra Ciucci & Ilaria De Stefano & Valerio Gaetano Vellone & Lucia Lisi & Carolina Bottoni & Giovanni Scambia & Gian Franco Zannoni & Daniela Gallo, 2013. "Expression of the Glioma-Associated Oncogene Homolog 1 (Gli1) in Advanced Serous Ovarian Cancer Is Associated with Unfavorable Overall Survival," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-9, March.
    3. Meropi Bagka & Hyeonyi Choi & Margaux Héritier & Hanna Schwaemmle & Quentin T. L. Pasquer & Simon M. G. Braun & Leonardo Scapozza & Yibo Wu & Sascha Hoogendoorn, 2023. "Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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