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Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma
The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCF(Fbxo4) complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses re...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688124/ https://www.ncbi.nlm.nih.gov/pubmed/29142209 http://dx.doi.org/10.1038/s41467-017-01199-8 |
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author | Qie, Shuo Majumder, Mrinmoyee Mackiewicz, Katarzyna Howley, Breege V. Peterson, Yuri K. Howe, Philip H. Palanisamy, Viswanathan Diehl, J. Alan |
author_facet | Qie, Shuo Majumder, Mrinmoyee Mackiewicz, Katarzyna Howley, Breege V. Peterson, Yuri K. Howe, Philip H. Palanisamy, Viswanathan Diehl, J. Alan |
author_sort | Qie, Shuo |
collection | PubMed |
description | The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCF(Fbxo4) complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCF(Fbxo4). Consistent with a substrate relationship, Fxr1 is overexpressed in Fbxo4 knockout cells, tissues and in human cancer cells, harbouring inactivating Fbxo4 mutations. Critically, in head and neck squamous cell carcinoma, Fxr1 overexpression correlates with reduced Fbxo4 levels in the absence of mutations or loss of mRNA, suggesting the potential for feedback regulation. Direct analysis reveals that Fbxo4 translation is attenuated by Fxr1, indicating the existence of a feedback loop that contributes to Fxr1 overexpression and the loss of Fbxo4. Ultimately, the consequence of Fxr1 overexpression is the bypass of senescence and neoplastic progression. |
format | Online Article Text |
id | pubmed-5688124 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56881242017-11-17 Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma Qie, Shuo Majumder, Mrinmoyee Mackiewicz, Katarzyna Howley, Breege V. Peterson, Yuri K. Howe, Philip H. Palanisamy, Viswanathan Diehl, J. Alan Nat Commun Article The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCF(Fbxo4) complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCF(Fbxo4). Consistent with a substrate relationship, Fxr1 is overexpressed in Fbxo4 knockout cells, tissues and in human cancer cells, harbouring inactivating Fbxo4 mutations. Critically, in head and neck squamous cell carcinoma, Fxr1 overexpression correlates with reduced Fbxo4 levels in the absence of mutations or loss of mRNA, suggesting the potential for feedback regulation. Direct analysis reveals that Fbxo4 translation is attenuated by Fxr1, indicating the existence of a feedback loop that contributes to Fxr1 overexpression and the loss of Fbxo4. Ultimately, the consequence of Fxr1 overexpression is the bypass of senescence and neoplastic progression. Nature Publishing Group UK 2017-11-16 /pmc/articles/PMC5688124/ /pubmed/29142209 http://dx.doi.org/10.1038/s41467-017-01199-8 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Qie, Shuo Majumder, Mrinmoyee Mackiewicz, Katarzyna Howley, Breege V. Peterson, Yuri K. Howe, Philip H. Palanisamy, Viswanathan Diehl, J. Alan Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma |
title | Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma |
title_full | Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma |
title_fullStr | Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma |
title_full_unstemmed | Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma |
title_short | Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma |
title_sort | fbxo4-mediated degradation of fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688124/ https://www.ncbi.nlm.nih.gov/pubmed/29142209 http://dx.doi.org/10.1038/s41467-017-01199-8 |
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