Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.

PloS One
Wen-Bin TsaiMickey C T Hu

Abstract

The ubiquitin-proteasome system is the primary proteolysis machine for controlling protein stability of the majority of regulatory proteins including those that are critical for cancer development. The forkhead box transcription factor FOXO3 plays a key role in regulating tumor suppression; however, the control of FOXO3 protein stability remains to be established. It is crucial to elucidate the molecular mechanisms underlying the ubiquitin-mediated degradation of FOXO3 tumor suppressor. Here we show that betaTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkappaB kinase-beta phosphorylation dependent manner. Silencing betaTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing betaTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing betaTrCP1 promotes tumorigenesis and tumor growth in vivo. This is a unique demonstration that the betaTrCP1-mediated FOXO3 degradation plays a crucial role in tumorigenesis. These findings significantly contribute to understanding of the control of FOXO3 stability in cancer cells and may provide opportunities for d...Continue Reading

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Citations

Jun 21, 2014·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·María Paula CeballosMaría Cristina Carrillo
Sep 14, 2011·Cancer Research·Jen-Liang SuMien-Chie Hung
Jun 2, 2012·Frontiers in Bioscience (Landmark Edition)·Alan W LauWenyi Wei
Sep 18, 2012·Antioxidants & Redox Signaling·Paraskevi Charitou, Boudewijn M T Burgering
Dec 23, 2015·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Jianfei Qi, Ze'ev A Ronai
Jun 14, 2016·Cell Division·Danrui CuiYongchao Zhao
Dec 16, 2017·Nature Reviews. Cancer·Daniela SenftZe'ev A Ronai
Aug 7, 2014·International Journal of Oncology·See-Hyoung ParkMickey C-T Hu
May 21, 2020·Cancers·Kanae YumimotoKeiichi I Nakayama
Oct 7, 2020·The FEBS Journal·Yanli BiYongchao Zhao
Nov 2, 2020·Cell Death and Differentiation·Fabin DangWenyi Wei
Apr 11, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Bing LiuZhijuan Ren

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Methods Mentioned

BETA
gene knockouts
nuclear translocation
co-immunoprecipitation
ubiquitination
fluorescence microscopy
transfection
pull-down
electrophoresis
flow cytometry
xenograft

Software Mentioned

Graphpad

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