Identification of select glucocorticoids as Smoothened agonists: Potential utility for regenerative medicine

Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation. The development of Hedgehog-related therapies has been impede...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-05, Vol.107 (20), p.9323-9328
Main Authors: Wang, Jiangbo, Lu, Jiuyi, Bond, Michael C., Chen, Minyong, Ren, Xiu-Rong, Lyerly, H. Kim, Barak, Larry S., Chen, Wei, Lefkowitz, Robert J.
Format: Article
Language:English
Subjects:
Agonists
Androstadienes - pharmacology
Arrestins
beta-Arrestins
Biological Sciences
Blotting, Western
Cell growth
Cell Line
Cell Proliferation
Clobetasol - pharmacology
Drugs
Fluocinonide - pharmacology
Fluticasone
Glucocorticoids
Glucocorticoids - pharmacology
Green Fluorescent Proteins
Halcinonide - pharmacology
Hedgehog Proteins - metabolism
HEK293 cells
Humans
Internalization
Membranes
Molecular Structure
Neural stem cells
Neurons
Proteins
Receptors
Receptors, G-Protein-Coupled - agonists
Regenerative medicine
Regenerative Medicine - methods
Signal Transduction - physiology
Smoothened Receptor
Stem cells
Stem Cells - metabolism
Stem Cells - physiology
Steroids
Tissues
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Summary:Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation. The development of Hedgehog-related therapies has been impeded by a lack of US Food and Drug Administration (FDA)-approved Smo agonists. Using a high-content screen with cells expressing Smo receptors and a β-arrestin2-GFP reporter, we identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. These drugs demonstrated an ability to bind Smo, promote Smo internalization, activate Gli, and stimulate the proliferation of primary neuronal precursor cells alone and synergistically in the presence of Sonic Hedgehog protein. Halcinonide, fluticasone, clobetasol, and fluocinonide provide an unprecedented opportunity to develop unique clinical strategies to treat Hedgehog-dependent illnesses.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0910712107