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

<h4>Background</h4>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 regulat...

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Autores principales:	Wen-Bin Tsai, Young Min Chung, Yiyu Zou, See-Hyoung Park, Zhaohui Xu, Keiko Nakayama, Sue-Hwa Lin, Mickey C-T Hu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b0b03a58f4694d64a18c291c09a85f5e
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spelling	oai:doaj.org-article:b0b03a58f4694d64a18c291c09a85f5e2021-12-02T20:20:19ZInhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.1932-620310.1371/journal.pone.0011171https://doaj.org/article/b0b03a58f4694d64a18c291c09a85f5e2010-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20625400/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology and principal findings</h4>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.<h4>Conclusions/significance</h4>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 developing innovative anticancer therapeutic modalities.Wen-Bin TsaiYoung Min ChungYiyu ZouSee-Hyoung ParkZhaohui XuKeiko NakayamaSue-Hwa LinMickey C-T HuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 7, p e11171 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wen-Bin Tsai Young Min Chung Yiyu Zou See-Hyoung Park Zhaohui Xu Keiko Nakayama Sue-Hwa Lin Mickey C-T Hu Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.
description	<h4>Background</h4>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.<h4>Methodology and principal findings</h4>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.<h4>Conclusions/significance</h4>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 developing innovative anticancer therapeutic modalities.
format	article
author	Wen-Bin Tsai Young Min Chung Yiyu Zou See-Hyoung Park Zhaohui Xu Keiko Nakayama Sue-Hwa Lin Mickey C-T Hu
author_facet	Wen-Bin Tsai Young Min Chung Yiyu Zou See-Hyoung Park Zhaohui Xu Keiko Nakayama Sue-Hwa Lin Mickey C-T Hu
author_sort	Wen-Bin Tsai
title	Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.
title_short	Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.
title_full	Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.
title_fullStr	Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.
title_full_unstemmed	Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.
title_sort	inhibition of foxo3 tumor suppressor function by betatrcp1 through ubiquitin-mediated degradation in a tumor mouse model.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/b0b03a58f4694d64a18c291c09a85f5e
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Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.

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