| Project/Area Number |
18591824
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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 | The University of Tokyo |
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Principal Investigator |
NAKAGAWA Shunsuke The University of Tokyo, Faculty of Medicine, Lecturer (70270874)
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| Co-Investigator(Kenkyū-buntansha) |
YANO Tetsu The University of Tokyo, Faculty of Medicine, Associate Professor (90251264)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Apoptosis / tumor suppressor / human papillomavirus / ubiquitination / E6 oncoprotein / 新規癌抑制遺伝子 / 子宮頸部腺癌 |
|---|
| Research Abstract |
Inactivation of tumor suppressor proteins involving in cell cycle regulation and apoptosis through ubiquitin-mediated degradation by human papillomavirus (HPV) E6 oncoprotein and ubiquitin-proteasome is a critical step in cervical carcinogenesis. Here, we show that HPV E6 targets the product of dbc-1 (deleted in breast cancer-1) gene, which was identified from homozygously deleted region in breast cancers on human chromosome 8p21, for ubiquitin-mediated degradation. DBC-1 interacts with both low- and high-risk HPV E6s, but its binding ability with low-risk E6 was weaker. Mutational analysis showed that E6 binds 700-750 amino acids region of DBC-1. In vitro translated DBC-1 with rabbit reticulocyte lysate but not that translated with wheat germ extract was degraded in the presence of high-risk E6. HPV 16 E6 stimulated in vitro ubiquitination of DBC-1 in the presence of ATP γ S. Transfection of high-risk E6 expression vector into 293 T cells induces ubiquitin-mediated degradation of DBC-1. Addition of proteasomal inhibitor MG132 or RNAi against E6AP recovered the DBC-1 expression in HPV-positive Caski cells. DBC-1 localized in nucleus in healthy cells, but concentrated in mitochondria during apoptosis induced by etoposide. Progressive loss of DBC-1 expression is observed during process of cervical carcinogenesis from normal cervical epithelia to invasive cervical cancer. These data suggest the possibility that degradation of DBC-1 by E6-E6AP might have a critical role in inhibition of apoptotic signal pathway in mitochondria during cervical carcinogenesis.
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