Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.
Nature
; 406(6799): 1005-9, 2000 Aug 31.
Article
en En
| MEDLINE
| ID: mdl-10984056
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Alcaloides de Veratrum
/
Transducción de Señal
/
Proteínas
/
Transactivadores
/
Receptores de Superficie Celular
/
Proteínas de Drosophila
/
Receptores Acoplados a Proteínas G
/
Proteínas de la Membrana
/
Antineoplásicos Fitogénicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nature
Año:
2000
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido