The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation an...

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Autores principales: Xu, Jie, Zhou, Weihua, Yang, Fei, Chen, Guoan, Li, Haomin, Zhao, Yongchao, Liu, Pengyuan, Li, Hua, Tan, Mingjia, Xiong, Xiufang, Sun, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241824/
https://www.ncbi.nlm.nih.gov/pubmed/28090088
http://dx.doi.org/10.1038/ncomms14002
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author Xu, Jie
Zhou, Weihua
Yang, Fei
Chen, Guoan
Li, Haomin
Zhao, Yongchao
Liu, Pengyuan
Li, Hua
Tan, Mingjia
Xiong, Xiufang
Sun, Yi
author_facet Xu, Jie
Zhou, Weihua
Yang, Fei
Chen, Guoan
Li, Haomin
Zhao, Yongchao
Liu, Pengyuan
Li, Hua
Tan, Mingjia
Xiong, Xiufang
Sun, Yi
author_sort Xu, Jie
collection PubMed
description β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation.
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spelling pubmed-52418242017-02-02 The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor Xu, Jie Zhou, Weihua Yang, Fei Chen, Guoan Li, Haomin Zhao, Yongchao Liu, Pengyuan Li, Hua Tan, Mingjia Xiong, Xiufang Sun, Yi Nat Commun Article β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation. Nature Publishing Group 2017-01-16 /pmc/articles/PMC5241824/ /pubmed/28090088 http://dx.doi.org/10.1038/ncomms14002 Text en Copyright © 2017, The Author(s) 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
Xu, Jie
Zhou, Weihua
Yang, Fei
Chen, Guoan
Li, Haomin
Zhao, Yongchao
Liu, Pengyuan
Li, Hua
Tan, Mingjia
Xiong, Xiufang
Sun, Yi
The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
title The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
title_full The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
title_fullStr The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
title_full_unstemmed The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
title_short The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
title_sort β-trcp-fbxw2-skp2 axis regulates lung cancer cell growth with fbxw2 acting as a tumour suppressor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241824/
https://www.ncbi.nlm.nih.gov/pubmed/28090088
http://dx.doi.org/10.1038/ncomms14002
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