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Genetic screening reveals a link between Wnt signaling and antitubulin drugs

The antitubulin drugs, paclitaxel (PX) and colchicine (COL), inhibit cell growth and are therapeutically valuable. PX stabilizes microtubules, while COL promotes their depolymerization. But, the drug concentrations that alter tubulin polymerization are hundreds of times higher than their clinically...

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Autores principales: Khan, A H, Bloom, J S, Faridmoayer, E, Smith, D J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705004/
https://www.ncbi.nlm.nih.gov/pubmed/26149735
http://dx.doi.org/10.1038/tpj.2015.50
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author Khan, A H
Bloom, J S
Faridmoayer, E
Smith, D J
author_facet Khan, A H
Bloom, J S
Faridmoayer, E
Smith, D J
author_sort Khan, A H
collection PubMed
description The antitubulin drugs, paclitaxel (PX) and colchicine (COL), inhibit cell growth and are therapeutically valuable. PX stabilizes microtubules, while COL promotes their depolymerization. But, the drug concentrations that alter tubulin polymerization are hundreds of times higher than their clinically useful levels. To map genetic targets for drug action at single-gene resolution, we used a human radiation hybrid panel. We identified loci that affected cell survival in the presence of five compounds of medical relevance. For PX and COL, the zinc and ring finger 3 (ZNRF3) gene dominated the genetic landscape at therapeutic concentrations. ZNRF3 encodes an R-spondin regulated receptor that inhibits Wingless/Int (Wnt) signaling. Overexpression of the ZNRF3 gene shielded cells from antitubulin drug action, while small interfering RNA knockdowns resulted in sensitization. Further a potent pharmacological inhibitor of Wnt signaling, Wnt-C59, protected cells from PX and COL. Our results suggest that the antitubulin drugs perturb microtubule dynamics, thereby influencing Wnt signaling.
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spelling pubmed-47050042016-04-17 Genetic screening reveals a link between Wnt signaling and antitubulin drugs Khan, A H Bloom, J S Faridmoayer, E Smith, D J Pharmacogenomics J Original Article The antitubulin drugs, paclitaxel (PX) and colchicine (COL), inhibit cell growth and are therapeutically valuable. PX stabilizes microtubules, while COL promotes their depolymerization. But, the drug concentrations that alter tubulin polymerization are hundreds of times higher than their clinically useful levels. To map genetic targets for drug action at single-gene resolution, we used a human radiation hybrid panel. We identified loci that affected cell survival in the presence of five compounds of medical relevance. For PX and COL, the zinc and ring finger 3 (ZNRF3) gene dominated the genetic landscape at therapeutic concentrations. ZNRF3 encodes an R-spondin regulated receptor that inhibits Wingless/Int (Wnt) signaling. Overexpression of the ZNRF3 gene shielded cells from antitubulin drug action, while small interfering RNA knockdowns resulted in sensitization. Further a potent pharmacological inhibitor of Wnt signaling, Wnt-C59, protected cells from PX and COL. Our results suggest that the antitubulin drugs perturb microtubule dynamics, thereby influencing Wnt signaling. Nature Publishing Group 2016-04 2015-07-07 /pmc/articles/PMC4705004/ /pubmed/26149735 http://dx.doi.org/10.1038/tpj.2015.50 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Original Article
Khan, A H
Bloom, J S
Faridmoayer, E
Smith, D J
Genetic screening reveals a link between Wnt signaling and antitubulin drugs
title Genetic screening reveals a link between Wnt signaling and antitubulin drugs
title_full Genetic screening reveals a link between Wnt signaling and antitubulin drugs
title_fullStr Genetic screening reveals a link between Wnt signaling and antitubulin drugs
title_full_unstemmed Genetic screening reveals a link between Wnt signaling and antitubulin drugs
title_short Genetic screening reveals a link between Wnt signaling and antitubulin drugs
title_sort genetic screening reveals a link between wnt signaling and antitubulin drugs
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705004/
https://www.ncbi.nlm.nih.gov/pubmed/26149735
http://dx.doi.org/10.1038/tpj.2015.50
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