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

Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA
Nature. 2000 406 (6799): 1005-9

PMID: 10984056 · DOI:10.1038/35023008

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 pathway. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response, 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.

MeSH Terms (26)

3T3 Cells Animals Antineoplastic Agents, Phytogenic Basal Cell Nevus Syndrome Cell Line Cell Transformation, Neoplastic Cloning, Molecular Drosophila Drosophila Proteins Gene Expression Regulation Hedgehog Proteins Humans Intracellular Signaling Peptides and Proteins Membrane Proteins Mice Mutation Oncogenes Patched-1 Receptor Patched Receptors Proteins Receptors, Cell Surface Receptors, G-Protein-Coupled Signal Transduction Smoothened Receptor Trans-Activators Veratrum Alkaloids

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