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

Jussi Taipale, James K. Chen, Michael K. Cooper, Baolin Wang, Randall K. Mann, Ljiljana Milenkovic, Matthew P. Scott and Philip A. Beachy ()
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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
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

Nature, 2000, vol. 406, issue 6799, 1005-1009

Abstract: 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.

Date: 2000
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DOI: 10.1038/35023008

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