| Literature DB >> 30340023 |
David R Raleigh1, Navdar Sever2, Pervinder K Choksi3, Monika Abedin Sigg4, Kelly M Hines5, Bonne M Thompson6, Daniel Elnatan4, Priyadarshini Jaishankar7, Paola Bisignano8, Francesc R Garcia-Gonzalo4, Alexis Leigh Krup3, Markus Eberl9, Eamon F X Byrne10, Christian Siebold10, Sunny Y Wong9, Adam R Renslo7, Michael Grabe8, Jeffrey G McDonald11, Libin Xu5, Philip A Beachy12, Jeremy F Reiter13.
Abstract
Primary cilia are required for Smoothened to transduce vertebrate Hedgehog signals, but how Smoothened accumulates in cilia and is activated is incompletely understood. Here, we identify cilia-associated oxysterols that promote Smoothened accumulation in cilia and activate the Hedgehog pathway. Our data reveal that cilia-associated oxysterols bind to two distinct Smoothened domains to modulate Smoothened accumulation in cilia and tune the intensity of Hedgehog pathway activation. We find that the oxysterol synthase HSD11β2 participates in the production of Smoothened-activating oxysterols and promotes Hedgehog pathway activity. Inhibiting oxysterol biosynthesis impedes oncogenic Hedgehog pathway activation and attenuates the growth of Hedgehog pathway-associated medulloblastoma, suggesting that targeted inhibition of Smoothened-activating oxysterol production may be therapeutically useful for patients with Hedgehog-associated cancers. Published by Elsevier Inc.Entities:
Keywords: CBP; HSD11β2; Hedgehog; Smoothened; cilia; lipid; medulloblastoma; oxysterol; primary cilium; sterol
Mesh：
Substances：
Year: 2018 PMID： 30340023 PMCID： PMC6503851 DOI： 10.1016/j.molcel.2018.08.034
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970