Contribution of estrogen receptor α to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway

Kiyoko Kato, Shinji Horiuchi, Akira Takahashi, Yousuke Ueoka, Takahiro Arima, Takao Matsuda, Hidenori Kato, Jun Ichi Nishida, Yusaku Nakabeppu, Norio Wake

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

We previously reported that enhanced transcriptional activation of estrogen receptor α (ERα) contributed to [ 12Val]K-Ras-mediated NIH3T3 cell transformation. Functional inactivation of ERα by a dominant negative mutant of ERα (DNER) in the presence of activated K-Ras 4B mutant arrested the cell cycle at G 0/G 1, subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent upregulation of p21 was implicated in this cell senescence induction. Alterations in the MDM2 protein in response to DNER accounted for this p21-mediated cell senescence induction. An oncogenic K-Ras 4B mutant significantly increased MDM2 proteins coprecipitated with p53, and suppressed p53 transcriptional activity. In turn, DNER exerted its function to decrease MDM2 proteins coprecipitated with p53, followed by the stimulation of p53 activity in the presence of the oncogenic K-Ras 4B mutant. In addition, overexpression of wild type ERα in NIH3T3 cells resulted in the significant increase in the MDM2 protein level and the resultant suppression of p53 transcriptional activity. Finally, we demonstrated that c-Jun expression overcame the suppression and resultant enhancement of p21 protein level in response to DNER. The data imply that the ERα-AP1 pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.

Original languageEnglish
Pages (from-to)11217-11224
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number13
DOIs
Publication statusPublished - Mar 29 2002

Fingerprint

Estrogen Receptors
Cell Aging
Proteins
Transcriptional Activation
Cell Cycle
Up-Regulation
Chemical activation
Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Contribution of estrogen receptor α to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway. / Kato, Kiyoko; Horiuchi, Shinji; Takahashi, Akira; Ueoka, Yousuke; Arima, Takahiro; Matsuda, Takao; Kato, Hidenori; Nishida, Jun Ichi; Nakabeppu, Yusaku; Wake, Norio.

In: Journal of Biological Chemistry, Vol. 277, No. 13, 29.03.2002, p. 11217-11224.

Research output: Contribution to journalArticle

Kato, Kiyoko ; Horiuchi, Shinji ; Takahashi, Akira ; Ueoka, Yousuke ; Arima, Takahiro ; Matsuda, Takao ; Kato, Hidenori ; Nishida, Jun Ichi ; Nakabeppu, Yusaku ; Wake, Norio. / Contribution of estrogen receptor α to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 13. pp. 11217-11224.
@article{e85d3e4ffe8c4805b4e64cb08dbcf9ca,
title = "Contribution of estrogen receptor α to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway",
abstract = "We previously reported that enhanced transcriptional activation of estrogen receptor α (ERα) contributed to [ 12Val]K-Ras-mediated NIH3T3 cell transformation. Functional inactivation of ERα by a dominant negative mutant of ERα (DNER) in the presence of activated K-Ras 4B mutant arrested the cell cycle at G 0/G 1, subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent upregulation of p21 was implicated in this cell senescence induction. Alterations in the MDM2 protein in response to DNER accounted for this p21-mediated cell senescence induction. An oncogenic K-Ras 4B mutant significantly increased MDM2 proteins coprecipitated with p53, and suppressed p53 transcriptional activity. In turn, DNER exerted its function to decrease MDM2 proteins coprecipitated with p53, followed by the stimulation of p53 activity in the presence of the oncogenic K-Ras 4B mutant. In addition, overexpression of wild type ERα in NIH3T3 cells resulted in the significant increase in the MDM2 protein level and the resultant suppression of p53 transcriptional activity. Finally, we demonstrated that c-Jun expression overcame the suppression and resultant enhancement of p21 protein level in response to DNER. The data imply that the ERα-AP1 pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.",
author = "Kiyoko Kato and Shinji Horiuchi and Akira Takahashi and Yousuke Ueoka and Takahiro Arima and Takao Matsuda and Hidenori Kato and Nishida, {Jun Ichi} and Yusaku Nakabeppu and Norio Wake",
year = "2002",
month = "3",
day = "29",
doi = "10.1074/jbc.M107391200",
language = "English",
volume = "277",
pages = "11217--11224",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "13",

}

TY - JOUR

T1 - Contribution of estrogen receptor α to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway

AU - Kato, Kiyoko

AU - Horiuchi, Shinji

AU - Takahashi, Akira

AU - Ueoka, Yousuke

AU - Arima, Takahiro

AU - Matsuda, Takao

AU - Kato, Hidenori

AU - Nishida, Jun Ichi

AU - Nakabeppu, Yusaku

AU - Wake, Norio

PY - 2002/3/29

Y1 - 2002/3/29

N2 - We previously reported that enhanced transcriptional activation of estrogen receptor α (ERα) contributed to [ 12Val]K-Ras-mediated NIH3T3 cell transformation. Functional inactivation of ERα by a dominant negative mutant of ERα (DNER) in the presence of activated K-Ras 4B mutant arrested the cell cycle at G 0/G 1, subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent upregulation of p21 was implicated in this cell senescence induction. Alterations in the MDM2 protein in response to DNER accounted for this p21-mediated cell senescence induction. An oncogenic K-Ras 4B mutant significantly increased MDM2 proteins coprecipitated with p53, and suppressed p53 transcriptional activity. In turn, DNER exerted its function to decrease MDM2 proteins coprecipitated with p53, followed by the stimulation of p53 activity in the presence of the oncogenic K-Ras 4B mutant. In addition, overexpression of wild type ERα in NIH3T3 cells resulted in the significant increase in the MDM2 protein level and the resultant suppression of p53 transcriptional activity. Finally, we demonstrated that c-Jun expression overcame the suppression and resultant enhancement of p21 protein level in response to DNER. The data imply that the ERα-AP1 pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.

AB - We previously reported that enhanced transcriptional activation of estrogen receptor α (ERα) contributed to [ 12Val]K-Ras-mediated NIH3T3 cell transformation. Functional inactivation of ERα by a dominant negative mutant of ERα (DNER) in the presence of activated K-Ras 4B mutant arrested the cell cycle at G 0/G 1, subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent upregulation of p21 was implicated in this cell senescence induction. Alterations in the MDM2 protein in response to DNER accounted for this p21-mediated cell senescence induction. An oncogenic K-Ras 4B mutant significantly increased MDM2 proteins coprecipitated with p53, and suppressed p53 transcriptional activity. In turn, DNER exerted its function to decrease MDM2 proteins coprecipitated with p53, followed by the stimulation of p53 activity in the presence of the oncogenic K-Ras 4B mutant. In addition, overexpression of wild type ERα in NIH3T3 cells resulted in the significant increase in the MDM2 protein level and the resultant suppression of p53 transcriptional activity. Finally, we demonstrated that c-Jun expression overcame the suppression and resultant enhancement of p21 protein level in response to DNER. The data imply that the ERα-AP1 pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.

UR - http://www.scopus.com/inward/record.url?scp=0037192779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037192779&partnerID=8YFLogxK

U2 - 10.1074/jbc.M107391200

DO - 10.1074/jbc.M107391200

M3 - Article

C2 - 11781307

AN - SCOPUS:0037192779

VL - 277

SP - 11217

EP - 11224

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 13

ER -