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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-01-16

AUTHORS

Jie Xu, Weihua Zhou, Fei Yang, Guoan Chen, Haomin Li, Yongchao Zhao, Pengyuan Liu, Hua Li, Mingjia Tan, Xiufang Xiong, Yi Sun

ABSTRACT

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. More... »

PAGES

14002

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms14002

DOI

http://dx.doi.org/10.1038/ncomms14002

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1025155627

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28090088


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36 schema:description Abstractβ-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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43 F-box
44 F-box proteins
45 FBXW2
46 Skp2
47 Skp2 degradation
48 activity
49 axis
50 better patient survival
51 cancer
52 cancer cell growth
53 cancer cells
54 cascade
55 cell cycle
56 cell growth
57 cells
58 cycle
59 data
60 degradation
61 function
62 function mutations
63 growth
64 human cancers
65 levels
66 ligase
67 loss
68 lung cancer cell growth
69 lung cancer cells
70 mutations
71 oncogene
72 oncogenic function
73 opposite
74 patient survival
75 protein
76 substrate
77 suppressor
78 suppressor activity
79 survival
80 tumor suppressor
81 tumor suppressor activity
82 ubiquitylation
83 worse survival
84 β-TrCP1
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