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Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability

Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics i...

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Autores principales: Thoma, Claudio R., Matov, Alexandre, Gutbrodt, Katrin L., Hoerner, Christian R., Smole, Zlatko, Krek, Wilhelm, Danuser, Gaudenz
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101603/
https://www.ncbi.nlm.nih.gov/pubmed/20855504
http://dx.doi.org/10.1083/jcb.201006059
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author Thoma, Claudio R.
Matov, Alexandre
Gutbrodt, Katrin L.
Hoerner, Christian R.
Smole, Zlatko
Krek, Wilhelm
Danuser, Gaudenz
author_facet Thoma, Claudio R.
Matov, Alexandre
Gutbrodt, Katrin L.
Hoerner, Christian R.
Smole, Zlatko
Krek, Wilhelm
Danuser, Gaudenz
author_sort Thoma, Claudio R.
collection PubMed
description Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics is unknown. We tracked MT growth via the plus end marker EB3 (end-binding protein 3)-GFP and inferred additional parameters of MT dynamics indirectly by spatiotemporal grouping of growth tracks from live cell imaging. Our data establish pVHL as a near-optimal MT-stabilizing protein: it attenuates tubulin turnover, both during MT growth and shrinkage, inhibits catastrophe, and enhances rescue frequencies. These functions are mediated, in part, by inhibition of tubulin guanosine triphosphatase activity in vitro and at MT plus ends and along the MT lattice in vivo. Mutants connected to the VHL cancer syndrome are differentially compromised in these activities. Thus, single cell–level analysis of pVHL MT regulatory function allows new predictions for genotype to phenotype associations that deviate from the coarser clinically defined mutant classifications.
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spelling pubmed-31016032011-06-06 Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability Thoma, Claudio R. Matov, Alexandre Gutbrodt, Katrin L. Hoerner, Christian R. Smole, Zlatko Krek, Wilhelm Danuser, Gaudenz J Cell Biol Research Articles Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics is unknown. We tracked MT growth via the plus end marker EB3 (end-binding protein 3)-GFP and inferred additional parameters of MT dynamics indirectly by spatiotemporal grouping of growth tracks from live cell imaging. Our data establish pVHL as a near-optimal MT-stabilizing protein: it attenuates tubulin turnover, both during MT growth and shrinkage, inhibits catastrophe, and enhances rescue frequencies. These functions are mediated, in part, by inhibition of tubulin guanosine triphosphatase activity in vitro and at MT plus ends and along the MT lattice in vivo. Mutants connected to the VHL cancer syndrome are differentially compromised in these activities. Thus, single cell–level analysis of pVHL MT regulatory function allows new predictions for genotype to phenotype associations that deviate from the coarser clinically defined mutant classifications. The Rockefeller University Press 2010-09-20 /pmc/articles/PMC3101603/ /pubmed/20855504 http://dx.doi.org/10.1083/jcb.201006059 Text en © 2010 Thoma et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Thoma, Claudio R.
Matov, Alexandre
Gutbrodt, Katrin L.
Hoerner, Christian R.
Smole, Zlatko
Krek, Wilhelm
Danuser, Gaudenz
Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability
title Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability
title_full Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability
title_fullStr Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability
title_full_unstemmed Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability
title_short Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability
title_sort quantitative image analysis identifies pvhl as a key regulator of microtubule dynamic instability
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101603/
https://www.ncbi.nlm.nih.gov/pubmed/20855504
http://dx.doi.org/10.1083/jcb.201006059
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