Document Detail

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis.
MedLine Citation:
PMID:  22864913     Owner:  NLM     Status:  MEDLINE    
Vertebrate Hedgehog (Hh) signals involved in development and some forms of cancer, such as basal cell carcinoma, are transduced by the primary cilium, a microtubular projection found on many cells. A critical step in vertebrate Hh signal transduction is the regulated movement of Smoothened (Smo), a seven-transmembrane protein, to the primary cilium. To identify small molecules that interfere with either the ciliary localization of Smo or ciliogenesis, we undertook a high-throughput, microscopy-based screen for compounds that alter the ciliary localization of YFP-tagged Smo. This screen identified 10 compounds that inhibit Hh pathway activity. Nine of these Smo antagonists (SA1-9) bind Smo, and one (SA10) does not. We also identified two compounds that inhibit ciliary biogenesis, which block microtubule polymerization or alter centrosome composition. Differential labeling of cell surface and intracellular Smo pools indicates that SA1-7 and 10 specifically inhibit trafficking of intracellular Smo to cilia. In contrast, SA8 and 9 recruit endogenous Smo to the cilium in some cell types. Despite these different mechanisms of action, all of the SAs inhibit activation of the Hh pathway by an oncogenic form of Smo, and abrogate the proliferation of basal cell carcinoma-like cancer cells. The SA compounds may provide alternative means of inhibiting pathogenic Hh signaling, and our study reveals that different pools of Smo move into cilia through distinct mechanisms.
Victoria M Wu; Steven C Chen; Michelle R Arkin; Jeremy F Reiter
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-03
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-22     Completed Date:  2012-10-31     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13644-9     Citation Subset:  IM    
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, School of Pharmacy, University of California, San Francisco, CA 95158, USA.
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MeSH Terms
Carcinoma, Basal Cell / metabolism*
Cell Line, Tumor
Cell Membrane / metabolism
Cell Proliferation
Cilia / metabolism
Cytoskeleton / metabolism
Dose-Response Relationship, Drug
Gene Expression Regulation, Neoplastic*
Inhibitory Concentration 50
Microtubules / metabolism
NIH 3T3 Cells
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction
Grant Support
Reg. No./Substance:
0/Receptors, G-Protein-Coupled; 0/SMO protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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