2005 Fiscal Year Final Research Report Summary
Crosstalk between estrogen receptor and transcriptional factors in the presence of SERM
| Project/Area Number |
15591726
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Yamagata University |
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Principal Investigator |
KOJIMAHARA Takanobu Yamagata University, School of Medicine, Assistant professor, 医学部, 助手 (20344806)
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| Co-Investigator(Kenkyū-buntansha) |
KURACHI Hirohisa Yamagata University, School of Medicine, Professor, 医学部, 教授 (40153366)
TAKAHASHI Kazuhiro Yamagata University, School of Medicine, Assistant professor, 医学部, 助手 (20292427)
IGARASHI Hideki Yamagata University, School of Medicine, Assistant professor, 医学部, 助手 (80333970)
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| Project Period (FY) |
2003 – 2005
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| Keywords | estrogen / selective estrogen receptor modulator (SERM) / GFP / FRET / EGF / IGF-1 / growth factor |
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| Research Abstract |
Initially, we intended to evaluate the interaction of estrogen receptor-alpha and coactivator or corepressor by using ER-alpha fused with GFP. People know that distribution of ER-alpha is changed by lignad, such as estrogen, within nucleus. In the initial year of this project, we found that distribution of ER-alpha fused with GFP was changed by epidermal growth factor (EGF) or insulin growth factor 1 (IGF-1), incidentally. This phenomenon seemed to be important for ligand-independent growth of estrogen-related tumor, which was resistant to hormone therapy. Therefore, we changed the purpose of the study to determine the mechanism of the phenomenon. The intranuclear distribution of ER-alpha was changed by estrogen, EGF and IGF-1, their time courses were different. Although, estrogen induced rapidly, within 5 min, the nuclear distribution of ER-alpha was changed, EGF or IGF-1 was changed the nuclear distribution of ER-alpha after 30 to 60 min. Neither changes of distribution of ER-alpha induced by estrogen, EGF or IGF-1 were seen in cells transfected with AF-2-deleted ER-alpha. The changes of nuclear distribution of ER-alpha induced by EGF or IGF-1 was prevented with MAP kinase or PI3 kinase inhibitors. Next, we determined that the transcriptional activity of ER-responsive gene by E2, EGF or IGF-1. E2 induced the increase of ER-responsive gene expression by using luciferase assay about 8 times higher tan control. EGF or IGF-1 also induced the 3 times increases of expression of ER-responsive gene. The expression of ER-responsive-gene induced by EGF or IGF-1 was inhibited in the pretreatement of MAP kinase or PI-3 kinase inhibitor. These results suggested that the changes of nuclear distribution of ER-alpha induced by growth factors, such as EGF or IGF-1 was involved via the MAP kianse or PI3 kinase pathway.
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