schliessen

Filtern

 

Bibliotheken

Gain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1

Many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that promote cancer cell invasive growth and metastasis, yet the mechanisms mediating these functions still largely remain elusive. We show here that overexpression of the GOF mutant p53 G245D and other GOF p53 mutants enhanc... Full description

Journal Title: Oncogene 2018, Vol.37(10), pp.1279-1292
Main Author: Tanaka, Noriaki
Other Authors: Zhao, Mei , Tang, Lin , Patel, Ameeta , Xi, Qing , Van, Hieu , Takahashi, Hideaki , Osman, Abdullah , Zhang, Jiexin , Wang, Jing , Myers, Jeffrey , Zhou, Ge
Format: Electronic Article Electronic Article
Language: English
Subjects:
P53
ID: ISSN: 0950-9232 ; DOI: 10.1038/s41388-017-0032-z
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: palgrave_j10.1038/s41388-017-0032-z
title: Gain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1
format: Article
creator:
  • Tanaka, Noriaki
  • Zhao, Mei
  • Tang, Lin
  • Patel, Ameeta
  • Xi, Qing
  • Van, Hieu
  • Takahashi, Hideaki
  • Osman, Abdullah
  • Zhang, Jiexin
  • Wang, Jing
  • Myers, Jeffrey
  • Zhou, Ge
subjects:
  • Article
  • P53
  • Mutant P53
  • Gain-Of-Function
  • Foxo3a
  • Foxm1
ispartof: Oncogene, 2018, Vol.37(10), pp.1279-1292
description: Many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that promote cancer cell invasive growth and metastasis, yet the mechanisms mediating these functions still largely remain elusive. We show here that overexpression of the GOF mutant p53 G245D and other GOF p53 mutants enhances the invasive cell growth of p53-deficient head and neck squamous cell carcinoma (HNSCC) UM-SCC-1 cells both in in vitro three-dimensional culture and in an in vivo orthotopic nude mouse model of HNSCC through a novel transcription-independent mechanism. We demonstrate that the expression of the oncogenic forkhead transcription factor FOXM1 is upregulated by GOF mutant p53s. Moreover, we show that overexpression of GOF mutant p53 G245D decreases the AMP-activated protein kinase (AMPK)-mediated phosphorylation of FOXO3a, a tumor suppressive forkhead transcription factor, leading to its cytoplasmic accumulation. This downregulation of FOXO3a’s activity, in turn, leads to de-repression of FOXM1 expression. Importantly, we show that either overexpression of FOXO3a or downregulation of FOXM1 impairs both GOF mutant p53-mediated cell invasion in vitro and pulmonary metastases of UM-SCC-1 cells in vivo. Finally, not only do oral cancer patients with p53 mutations exhibit higher levels of FOXM1 expression than patients with wild-type p53, but also HNSCC patients with TP53 mutations and high levels of FOXM1 expression have the poorest survival outcomes. Given our prior demonstration that GOF mutant p53s inhibit AMPK, our current study, establishes and demonstrates a novel transcription-independent GOF mutant p53-AMPK-FOXO3a-FOXM1 signaling cascade that plays an important role in mediating mutant p53s’ gain-of-function activities in HNSCCs.
language: eng
source:
identifier: ISSN: 0950-9232 ; DOI: 10.1038/s41388-017-0032-z
fulltext: fulltext
issn:
  • 0950-9232
  • 09509232
url: Link


@attributes
ID598208283
RANK0.07
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
LOCALfalse
PrimoNMBib
record
control
sourcerecordid10.1038/s41388-017-0032-z
sourceidpalgrave_j
recordidTN_palgrave_j10.1038/s41388-017-0032-z
sourcesystemPC
pqid1979965330
galeid572988973
display
typearticle
titleGain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1
creatorTanaka, Noriaki ; Zhao, Mei ; Tang, Lin ; Patel, Ameeta ; Xi, Qing ; Van, Hieu ; Takahashi, Hideaki ; Osman, Abdullah ; Zhang, Jiexin ; Wang, Jing ; Myers, Jeffrey ; Zhou, Ge
ispartofOncogene, 2018, Vol.37(10), pp.1279-1292
identifierISSN: 0950-9232 ; DOI: 10.1038/s41388-017-0032-z
descriptionMany mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that promote cancer cell invasive growth and metastasis, yet the mechanisms mediating these functions still largely remain elusive. We show here that overexpression of the GOF mutant p53 G245D and other GOF p53 mutants enhances the invasive cell growth of p53-deficient head and neck squamous cell carcinoma (HNSCC) UM-SCC-1 cells both in in vitro three-dimensional culture and in an in vivo orthotopic nude mouse model of HNSCC through a novel transcription-independent mechanism. We demonstrate that the expression of the oncogenic forkhead transcription factor FOXM1 is upregulated by GOF mutant p53s. Moreover, we show that overexpression of GOF mutant p53 G245D decreases the AMP-activated protein kinase (AMPK)-mediated phosphorylation of FOXO3a, a tumor suppressive forkhead transcription factor, leading to its cytoplasmic accumulation. This downregulation of FOXO3a’s activity, in turn, leads to de-repression of FOXM1 expression. Importantly, we show that either overexpression of FOXO3a or downregulation of FOXM1 impairs both GOF mutant p53-mediated cell invasion in vitro and pulmonary metastases of UM-SCC-1 cells in vivo. Finally, not only do oral cancer patients with p53 mutations exhibit higher levels of FOXM1 expression than patients with wild-type p53, but also HNSCC patients with TP53 mutations and high levels of FOXM1 expression have the poorest survival outcomes. Given our prior demonstration that GOF mutant p53s inhibit AMPK, our current study, establishes and demonstrates a novel transcription-independent GOF mutant p53-AMPK-FOXO3a-FOXM1 signaling cascade that plays an important role in mediating mutant p53s’ gain-of-function activities in HNSCCs.
languageeng
source
subjectArticle ; P53 ; Mutant P53 ; Gain-Of-Function ; Foxo3a ; Foxm1;
version8
lds50peer_reviewed
links
openurl$$Topenurl_article
openurlfulltext$$Topenurlfull_article
search
creatorcontrib
0Tanaka, Noriaki
1Zhao, Mei
2Tang, Lin
3Patel, Ameeta
4Xi, Qing
5Van, Hieu
6Takahashi, Hideaki
7Osman, Abdullah
8Zhang, Jiexin
9Wang, Jing
10Myers, Jeffrey
11Zhou, Ge
titleGain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1
descriptionMany mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that promote cancer cell invasive growth and metastasis, yet the mechanisms mediating these functions still largely remain elusive. We show here that overexpression of the GOF mutant p53 G245D and other GOF p53 mutants enhances the invasive cell growth of p53-deficient head and neck squamous cell carcinoma (HNSCC) UM-SCC-1 cells both in in vitro three-dimensional culture and in an in vivo orthotopic nude mouse model of HNSCC through a novel transcription-independent mechanism. We demonstrate that the expression of the oncogenic forkhead transcription factor FOXM1 is upregulated by GOF mutant p53s. Moreover, we show that overexpression of GOF mutant p53 G245D decreases the AMP-activated protein kinase (AMPK)-mediated phosphorylation of FOXO3a, a tumor suppressive forkhead transcription factor, leading to its cytoplasmic accumulation. This downregulation of FOXO3a’s activity, in turn, leads to de-repression of FOXM1 expression. Importantly, we show that either overexpression of FOXO3a or downregulation of FOXM1 impairs both GOF mutant p53-mediated cell invasion in vitro and pulmonary metastases of UM-SCC-1 cells in vivo. Finally, not only do oral cancer patients with p53 mutations exhibit higher levels of FOXM1 expression than patients with wild-type p53, but also HNSCC patients with TP53 mutations and high levels of FOXM1 expression have the poorest survival outcomes. Given our prior demonstration that GOF mutant p53s inhibit AMPK, our current study, establishes and demonstrates a novel transcription-independent GOF mutant p53-AMPK-FOXO3a-FOXM1 signaling cascade that plays an important role in mediating mutant p53s’ gain-of-function activities in HNSCCs.
general
0English
110.1038/s41388-017-0032-z
2Palgrave Macmillan Journals
sourceidpalgrave_j
recordidpalgrave_j10.1038/s41388-017-0032-z
issn
00950-9232
109509232
rsrctypearticle
creationdate2018
addtitleOncogene
searchscopepalgrave_j
scopepalgrave_j
lsr30VSR-Enriched:[galeid, eissn, pages, pqid, subject]
sort
titleGain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1
authorTanaka, Noriaki ; Zhao, Mei ; Tang, Lin ; Patel, Ameeta ; Xi, Qing ; Van, Hieu ; Takahashi, Hideaki ; Osman, Abdullah ; Zhang, Jiexin ; Wang, Jing ; Myers, Jeffrey ; Zhou, Ge
facets
frbrgroupid8842918799890721425
frbrtype5
newrecords20180314
languageeng
creationdate2018
collectionPalgrave Macmillan Journals
prefilterarticles
rsrctypearticles
creatorcontrib
0Tanaka, Noriaki
1Zhao, Mei
2Tang, Lin
3Patel, Ameeta
4Xi, Qing
5Van, Hieu
6Takahashi, Hideaki
7Osman, Abdullah
8Zhang, Jiexin
9Wang, Jing
10Myers, Jeffrey
11Zhou, Ge
jtitleOncogene
toplevelpeer_reviewed
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
aulast
0Tanaka
1Zhao
2Tang
3Patel
4Xi
5Van
6Takahashi
7Osman
8Zhang
9Wang
10Myers
11Zhou
aufirst
0Noriaki
1Mei
2Lin
3Ameeta
4Qing
5Hieu
6Hideaki
7Abdullah
8Jiexin
9Jing
10Jeffrey
11Ge
au
0Tanaka, Noriaki
1Zhao, Mei
2Tang, Lin
3Patel, Ameeta
4Xi, Qing
5Van, Hieu
6Takahashi, Hideaki
7Osman, Abdullah
8Zhang, Jiexin
9Wang, Jing
10Myers, Jeffrey
11Zhou, Ge
atitleGain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1
jtitleOncogene
date20183
risdate20183
volume37
issue10
spage1279
epage1292
issn0950-9232
formatjournal
genrearticle
ristypeJOUR
abstractMany mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that promote cancer cell invasive growth and metastasis, yet the mechanisms mediating these functions still largely remain elusive. We show here that overexpression of the GOF mutant p53 G245D and other GOF p53 mutants enhances the invasive cell growth of p53-deficient head and neck squamous cell carcinoma (HNSCC) UM-SCC-1 cells both in in vitro three-dimensional culture and in an in vivo orthotopic nude mouse model of HNSCC through a novel transcription-independent mechanism. We demonstrate that the expression of the oncogenic forkhead transcription factor FOXM1 is upregulated by GOF mutant p53s. Moreover, we show that overexpression of GOF mutant p53 G245D decreases the AMP-activated protein kinase (AMPK)-mediated phosphorylation of FOXO3a, a tumor suppressive forkhead transcription factor, leading to its cytoplasmic accumulation. This downregulation of FOXO3a’s activity, in turn, leads to de-repression of FOXM1 expression. Importantly, we show that either overexpression of FOXO3a or downregulation of FOXM1 impairs both GOF mutant p53-mediated cell invasion in vitro and pulmonary metastases of UM-SCC-1 cells in vivo. Finally, not only do oral cancer patients with p53 mutations exhibit higher levels of FOXM1 expression than patients with wild-type p53, but also HNSCC patients with TP53 mutations and high levels of FOXM1 expression have the poorest survival outcomes. Given our prior demonstration that GOF mutant p53s inhibit AMPK, our current study, establishes and demonstrates a novel transcription-independent GOF mutant p53-AMPK-FOXO3a-FOXM1 signaling cascade that plays an important role in mediating mutant p53s’ gain-of-function activities in HNSCCs.
pubNature Publishing Group UK
doi10.1038/s41388-017-0032-z
pages1279-1292
eissn14765594