Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity

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Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity

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Title: Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity
Author: McMahon, Andrew P.; Davidow, Lance Steven; Wang, Yu; Blanchard, Joel; Lam, Kelvin; Xu, Ke; Oza, Vatsal U.; Woo Yoo, Jin; Ng, Jessica; Curran, Tom; Rubin, Lee; Arvanites, Anthony

Note: Order does not necessarily reflect citation order of authors.

Citation: Wang, Yu, Lance Davidow, Anthony C. Arvanites, Joel Blanchard, Kelvin Lam, Ke Xu, Vatsal Oza et al. 2012. Glucocorticoid compounds modify smoothened localization and hedgehog pathway activity. Chemistry & Biology 19(8): 972-982.
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Abstract: The Hedgehog signaling pathway is linked to a variety of diseases, notably a range of cancers. The first generation of drug screens identified Smoothened (Smo), a membrane protein essential for signaling, as an attractive drug target. Smo localizes to the primary cilium upon pathway activation, and this transition is critical for the response to Hedgehog ligands. In a high content screen directly monitoring Smo distribution in Hedgehog-responsive cells, we identified different glucocorticoids as specific modulators of Smo ciliary accumulation. One class promoted Smo accumulation, conferring cellular hypersensitivity to Hedgehog stimulation. In contrast, a second class inhibited Smo ciliary localization and signaling activity by both wild-type Smo, and mutant forms of Smo, SmoM2, and SmoD473H, that are refractory to previously identified Smo antagonists. These findings point to the potential for developing glucocorticoid-based pharmacological modulation of Smo signaling to treat mutated drug-resistant forms of Smo, an emerging problem in long-term cancer therapy. They also raise a concern about potential crosstalk of glucocorticoid drugs in the Hedgehog pathway, if therapeutic administration exceeds levels associated with on-target transcriptional mechanisms of glucocorticoid action.
Published Version: doi:10.1016/j.chembiol.2012.06.012
Terms of Use: This article is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#OAP
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:9555244

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  • FAS Scholarly Articles [7105]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University
 
 

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