2007 Fiscal Year Final Research Report Summary
Identification of a new tumor suppressor protein involved in apoptosis and investigation of new treatment using the new tumor suppressor
| 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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| Keywords | Apoptosis / tumor suppressor / human papillomavirus / ubiquitination / E6 oncoprotein |
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| 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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Research Products
(18 results)
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[Journal Article] Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone2008
Author(s)
Zhao L, Yano T, Osuga Y, Nakagawa S, Oishi H, Wada-Hiraike O, Tang X, Yano N, Kugu K, Schally AV, Taketani Y.
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Journal Title
Int J Oncol 32(3)
Pages: 593-601
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Combined phospho-Akt and PTEN expressions associated with post-treatment hysterectomy after conservative progestin therapy in complex atypical hyperplasia and stage la, G1 adenocarcinoma of the endometrium2008
Author(s)
Minaguchi T, Nakagawa S, Takazawa Y, Nei T, Horie K, Fujiwara T, Osuga Y, Yasugi T, Kugu K, Yano T, Yoshikawa H, Taketani Y.
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Journal Title
Cancer Lett 248(1)
Pages: 112-22
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Loss of Hugl-1 expression associates with lymph node metastasis in endometrial cancer2007
Author(s)
Tsuruga T, Nakagawa S, Watanabe M, Takizawa S, Matsumoto Y, Nagasaka K, Sane K, Hiraike H, Miyamoto Y, Hiraike O, Minaguchi T, Oda K, Yasugi T, Yano T, Taketani Y.
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Journal Title
Oncol Res 16(9)
Pages: 431-5
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Human homolog of Drosophila tumor suppressor Scribble negatively regulates cell-cycle progression from G1 to S phase by localizing at the basolateral membrane in epithelial cells2006
Author(s)
Nagasaka K, Nakagawa S, Yano T, Takizawa S, Matsumoto Y, Tsuruga T, Nakagawa K, Minaguchi T, Oda K, Hiraike-Wada O, Ooishi H, Yasugi T, Taketani Y.
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Journal Title
Cancer Sci 97(11)
Pages: 1217-25
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli2006
Author(s)
Takizawa S, Nagasaka K, Nakagawa S, Yano T, Nakagawa K, Yasugi T, Takeuchi T, Kanda T, Huibregtse JM, Akiyama T, Taketani Y.
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Journal Title
Genes Cells 11(4)
Pages: 453-64
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E62006
Author(s)
Matsumoto Y, Nakagawa S, Yano T, Takizawa S, Nagasaka K, Nakagawa K, Minaguchi T, Wada O, Ooishi H, Matsumoto K, Yasugi T, Kanda T, Huibregtse JM, Taketani Y.
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Journal Title
J Med Virol 78(4)
Pages: 501-7
Description
「研究成果報告書概要(欧文)」より
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