| Project/Area Number |
12557138
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Kyushu University |
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Principal Investigator |
KATO Kiyoko Kyushu University, Medical Institute of Bioregulation Kyushu Univ. Lecturer, 生体防御医学研究所, 講師 (10253527)
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| Co-Investigator(Kenkyū-buntansha) |
WAKE Norio Kyushu University, Medical Institute of Bioregulation Kyushu Univ. Professor, 生体防御医学研究所, 教授 (50158606)
西田 純一 九州大学, 生体防御医学研究所, 助手 (40264113)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2001: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥6,900,000 (Direct Cost: ¥6,900,000)
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| Keywords | Ras / ER / tumorigenicity / Senescence / 造腫瘍能 / RAS |
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| Research Abstract |
We previously reported that enhanced transcriptional activation of estrogen receptorα(ERα) contributed to [^<12> Val] 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 G0/G1, subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent up-regulation 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-APl pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.
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