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A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway

Nitrilase1 was classified as a tumour suppressor in association with the fragile histidine-triad protein Fhit. However, knowledge about nitrilase1 and its tumour suppressor function is still limited. Whereas nitrilase1 and Fhit are discrete proteins in mammals, they are merged in Drosophila melanoga...

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Autores principales: Mittag, Sonnhild, Valenta, Tomas, Weiske, Jörg, Bloch, Laura, Klingel, Susanne, Gradl, Dietmar, Wetzel, Franziska, Chen, Yuan, Petersen, Iver, Basler, Konrad, Huber, Otmar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860965/
https://www.ncbi.nlm.nih.gov/pubmed/27462437
http://dx.doi.org/10.1038/celldisc.2015.39
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author Mittag, Sonnhild
Valenta, Tomas
Weiske, Jörg
Bloch, Laura
Klingel, Susanne
Gradl, Dietmar
Wetzel, Franziska
Chen, Yuan
Petersen, Iver
Basler, Konrad
Huber, Otmar
author_facet Mittag, Sonnhild
Valenta, Tomas
Weiske, Jörg
Bloch, Laura
Klingel, Susanne
Gradl, Dietmar
Wetzel, Franziska
Chen, Yuan
Petersen, Iver
Basler, Konrad
Huber, Otmar
author_sort Mittag, Sonnhild
collection PubMed
description Nitrilase1 was classified as a tumour suppressor in association with the fragile histidine-triad protein Fhit. However, knowledge about nitrilase1 and its tumour suppressor function is still limited. Whereas nitrilase1 and Fhit are discrete proteins in mammals, they are merged in Drosophila melanogaster and Caenorhabditis elegans. According to the Rosetta-Stone hypothesis, proteins encoded as fusion proteins in one organism and as separate proteins in another organism may act in the same signalling pathway. Although a direct interaction of human nitrilase1 and Fhit has not been shown, our previous finding that Fhit interacts with β-catenin and represses its transcriptional activity in the canonical Wnt pathway suggested that human nitrilase1 also modulates Wnt signalling. In fact, human nitrilase1 forms a complex with β-catenin and LEF-1/TCF-4, represses β-catenin-mediated transcription and shows an additive effect together with Fhit. Knockdown of human nitrilase1 enhances Wnt target gene expression. Moreover, our experiments show that β-catenin competes away human nitrilase1 from LEF-1/TCF and thereby contributes to the activation of Wnt-target gene transcription. Inhibitory activity of human nitrilase1 on vertebrate Wnt signalling was confirmed by repression of Wnt-induced double axis formation in Xenopus embryogenesis. In line with this finding, the Drosophila fusion protein Drosophila NitFhit directly binds to Armadillo and represses the Wingless pathway in reporter gene assays. Genetic experiments confirmed the repressive activity of Drosophila NitFhit on Wingless signalling in the Drosophila wing imaginal disc. In addition, colorectal tumour microarray analysis revealed a significantly reduced expression of human nitrilase1 in poorly differentiated tumours. Taken together, repression of the canonical Wnt pathway represents a new mechanism for the human nitrilase1 tumour suppressor function.
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spelling pubmed-48609652016-07-26 A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway Mittag, Sonnhild Valenta, Tomas Weiske, Jörg Bloch, Laura Klingel, Susanne Gradl, Dietmar Wetzel, Franziska Chen, Yuan Petersen, Iver Basler, Konrad Huber, Otmar Cell Discov Article Nitrilase1 was classified as a tumour suppressor in association with the fragile histidine-triad protein Fhit. However, knowledge about nitrilase1 and its tumour suppressor function is still limited. Whereas nitrilase1 and Fhit are discrete proteins in mammals, they are merged in Drosophila melanogaster and Caenorhabditis elegans. According to the Rosetta-Stone hypothesis, proteins encoded as fusion proteins in one organism and as separate proteins in another organism may act in the same signalling pathway. Although a direct interaction of human nitrilase1 and Fhit has not been shown, our previous finding that Fhit interacts with β-catenin and represses its transcriptional activity in the canonical Wnt pathway suggested that human nitrilase1 also modulates Wnt signalling. In fact, human nitrilase1 forms a complex with β-catenin and LEF-1/TCF-4, represses β-catenin-mediated transcription and shows an additive effect together with Fhit. Knockdown of human nitrilase1 enhances Wnt target gene expression. Moreover, our experiments show that β-catenin competes away human nitrilase1 from LEF-1/TCF and thereby contributes to the activation of Wnt-target gene transcription. Inhibitory activity of human nitrilase1 on vertebrate Wnt signalling was confirmed by repression of Wnt-induced double axis formation in Xenopus embryogenesis. In line with this finding, the Drosophila fusion protein Drosophila NitFhit directly binds to Armadillo and represses the Wingless pathway in reporter gene assays. Genetic experiments confirmed the repressive activity of Drosophila NitFhit on Wingless signalling in the Drosophila wing imaginal disc. In addition, colorectal tumour microarray analysis revealed a significantly reduced expression of human nitrilase1 in poorly differentiated tumours. Taken together, repression of the canonical Wnt pathway represents a new mechanism for the human nitrilase1 tumour suppressor function. Nature Publishing Group 2016-01-05 /pmc/articles/PMC4860965/ /pubmed/27462437 http://dx.doi.org/10.1038/celldisc.2015.39 Text en Copyright © 2016 SIBS, CAS http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 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/4.0/
spellingShingle Article
Mittag, Sonnhild
Valenta, Tomas
Weiske, Jörg
Bloch, Laura
Klingel, Susanne
Gradl, Dietmar
Wetzel, Franziska
Chen, Yuan
Petersen, Iver
Basler, Konrad
Huber, Otmar
A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway
title A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway
title_full A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway
title_fullStr A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway
title_full_unstemmed A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway
title_short A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway
title_sort novel role for the tumour suppressor nitrilase1 modulating the wnt/β-catenin signalling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860965/
https://www.ncbi.nlm.nih.gov/pubmed/27462437
http://dx.doi.org/10.1038/celldisc.2015.39
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