Showing papers by "Philip A. Beachy published in 2000"
TL;DR: It is shown that the plant-derived teratogen cyclopamine, which inhibits the Hh response, is a potential ‘mechanism-based’ therapeutic agent for treatment of these tumours.
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.
1,344 citations
TL;DR: It is demonstrated that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein.
1,035 citations
TL;DR: The disease holoprosencephaly is the basis of the most common structural anomaly of the developing forebrain in humans and numerous teratogens when administered during early gastrulation, have been associated with this condition.
253 citations
TL;DR: The mechanism of the Hedgehog autoprocessing reaction that results in modification of cholesterol, and the use of cholesterol as a molecular handle in the spatial deployment of the protein signal in developing tissues are reviewed.
111 citations
Patent•
13 Oct 2000TL;DR: In this paper, the authors present methods and reagents for modulating smoothened-dependent pathway activation, which can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway.
Abstract: The present invention makes available, inter alia, methods and reagents for modulating smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations.
61 citations