Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Academic Article uri icon

Overview

MeSH

  • 3T3 Cells
  • Animals
  • Basal Cell Nevus Syndrome
  • Cell Line
  • Cell Transformation, Neoplastic
  • Cloning, Molecular
  • Drosophila
  • Gene Expression Regulation
  • Hedgehog Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mutation
  • Oncogenes
  • Patched Receptors
  • Patched-1 Receptor
  • Smoothened Receptor

MeSH Major

  • Antineoplastic Agents, Phytogenic
  • Drosophila Proteins
  • Membrane Proteins
  • Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Signal Transduction
  • Trans-Activators
  • Veratrum Alkaloids

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 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.

publication date

  • August 31, 2000

has subject area

  • 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 Receptors
  • Patched-1 Receptor
  • Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Signal Transduction
  • Smoothened Receptor
  • Trans-Activators
  • Veratrum Alkaloids

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/35023008

PubMed ID

  • 10984056

Additional Document Info

start page

  • 1005

end page

  • 1009

volume

  • 406

number

  • 6799