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The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor. Nat Commun 2017 01 16;8:14002

Date

01/17/2017

Pubmed ID

28090088

Pubmed Central ID

PMC5241824

DOI

10.1038/ncomms14002

Scopus ID

2-s2.0-85009436123   30 Citations

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.

Author List

Xu J, Zhou W, Yang F, Chen G, Li H, Zhao Y, Liu P, Li H, Tan M, Xiong X, Sun Y

Author

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Cycle
Cell Line, Tumor
Cell Proliferation
F-Box Proteins
Female
Genes, Tumor Suppressor
Humans
Lung Neoplasms
Male
Mice
Mice, Nude
Proteolysis
S-Phase Kinase-Associated Proteins
beta-Transducin Repeat-Containing Proteins
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d