Inhibition of FOXO3 tumor suppressor function by βTrCP1 through ubiquitin-mediated degradation in a tumor mouse model

Wen Bin Tsai, Young Min Chung, Yiyu Zou, See Hyoung Park, Zhaohui Xu, Keiko Nakayama, Sue Hwa Lin, Mickey C T Hu

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: 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. Methodology and Principal Findings: Here we show that βTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkB kinase-p phosphorylation dependent manner. Silencing βTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing βTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing βTrCP1 promotes tumorigenesis and tumor growth in vivo. Conclusions/Significance: This is a unique demonstration that the βTrCP1-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.

Original languageEnglish (US)
Article numbere11171
JournalPLoS One
Volume5
Issue number7
DOIs
StatePublished - 2010

Fingerprint

ubiquitin
Ubiquitin
Tumors
animal models
carcinogenesis
Degradation
neoplasms
degradation
Neoplasms
Carcinogenesis
Proteins
proteins
Protein Stability
ubiquitin-protein ligase
Cells
boxes (containers)
Proteolysis
regulatory proteins
proteasome endopeptidase complex
Forkhead Transcription Factors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Inhibition of FOXO3 tumor suppressor function by βTrCP1 through ubiquitin-mediated degradation in a tumor mouse model. / Tsai, Wen Bin; Chung, Young Min; Zou, Yiyu; Park, See Hyoung; Xu, Zhaohui; Nakayama, Keiko; Lin, Sue Hwa; Hu, Mickey C T.

In: PLoS One, Vol. 5, No. 7, e11171, 2010.

Research output: Contribution to journalArticle

Tsai, Wen Bin ; Chung, Young Min ; Zou, Yiyu ; Park, See Hyoung ; Xu, Zhaohui ; Nakayama, Keiko ; Lin, Sue Hwa ; Hu, Mickey C T. / Inhibition of FOXO3 tumor suppressor function by βTrCP1 through ubiquitin-mediated degradation in a tumor mouse model. In: PLoS One. 2010 ; Vol. 5, No. 7.
@article{4d1476cfccca4429b1265c2f521f8162,
title = "Inhibition of FOXO3 tumor suppressor function by βTrCP1 through ubiquitin-mediated degradation in a tumor mouse model",
abstract = "Background: 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. Methodology and Principal Findings: Here we show that βTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkB kinase-p phosphorylation dependent manner. Silencing βTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing βTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing βTrCP1 promotes tumorigenesis and tumor growth in vivo. Conclusions/Significance: This is a unique demonstration that the βTrCP1-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.",
author = "Tsai, {Wen Bin} and Chung, {Young Min} and Yiyu Zou and Park, {See Hyoung} and Zhaohui Xu and Keiko Nakayama and Lin, {Sue Hwa} and Hu, {Mickey C T}",
year = "2010",
doi = "10.1371/journal.pone.0011171",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - Inhibition of FOXO3 tumor suppressor function by βTrCP1 through ubiquitin-mediated degradation in a tumor mouse model

AU - Tsai, Wen Bin

AU - Chung, Young Min

AU - Zou, Yiyu

AU - Park, See Hyoung

AU - Xu, Zhaohui

AU - Nakayama, Keiko

AU - Lin, Sue Hwa

AU - Hu, Mickey C T

PY - 2010

Y1 - 2010

N2 - Background: 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. Methodology and Principal Findings: Here we show that βTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkB kinase-p phosphorylation dependent manner. Silencing βTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing βTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing βTrCP1 promotes tumorigenesis and tumor growth in vivo. Conclusions/Significance: This is a unique demonstration that the βTrCP1-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.

AB - Background: 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. Methodology and Principal Findings: Here we show that βTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkB kinase-p phosphorylation dependent manner. Silencing βTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing βTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing βTrCP1 promotes tumorigenesis and tumor growth in vivo. Conclusions/Significance: This is a unique demonstration that the βTrCP1-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.

UR - http://www.scopus.com/inward/record.url?scp=77955366348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955366348&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0011171

DO - 10.1371/journal.pone.0011171

M3 - Article

C2 - 20625400

AN - SCOPUS:77955366348

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e11171

ER -