2006 Fiscal Year Final Research Report Summary
Identification of cervical adeno carcinoma related tumor suppressor using proteomic method
| Project/Area Number |
17591721
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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 |
YANO Tetsu The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (90251264)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAGAWA Shunsuke The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 助手 (70270874)
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| Project Period (FY) |
2005 – 2006
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| Keywords | cervical adeno carcinoma / human papillomavirus / proteomic approach / E6 oncoprotein / tumor suppressor / peptide mass finger print |
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| Research Abstract |
Human papillomavirus(HPV) is thought to have a causal role in cervical carcinogenesis. Approximately, in 95% of cervical cancer tissues, infection of HPV in found by wing DNA extracted from cancer tissues. HPV type 16 is the type of HPV most frequently identified from allover cervical cancer tissues, while HPV type 18 is the HPV type most frequently found in cervical adeno carcinoma, which represent about 10-20% of cervical cancer. Cervical adenocarcinoma is known to occur in younger women comparing with squamous cell carcinoma and to have poorer prognosis than squamous cell carcinoma. Given that each types of HPV infect to the cervical epithelia at the same age, HPV type 18 is thought to have stronger transforming ability than HPV type 16. HPV has two oncogenes, E6 and E7. E7 oncoprotein interacts with tumor suppressor pRb. While E6 oncoprotein interacts with tumor suppresser p53, it also degrade p53 through the ubiquitin-mediated pathway depending on the expression of E6AP, the cellu
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lar ubiquitin-protein ligase. Dr.Shunsuke Nakagawa, who is a member of this research, identified a new tumor suppressor protein human Scribble. Human Scribble is a human homologue of Drosophila tumor suppressor protein, which has a role in control of cellular apical-basolateral polarity. Loss of scribble mutation leads to the disruption of epithelial polarity and overgrowth of epithelia. Hunan Scribble has almost equivalent protein structure to its Drosophila homologue. The expression of human Scribble in Drosophila scribble mutant recovers phenotype of loss of cellular polarity and overgrowth of epithelia. These results indicate that human Scribble has a role in suppression of tumorgenesis. We tried to identify a new tumor suppressor protein related to the development of cervical adenocarcinoma. We identified the product of dbc-1(deleted in breast cancer-1) gene, which localizes on 8p21 and is frequently deleted among breast cancers, as a now ubiqituin-mediated degradation target of E6 oncoprotein. DBC1 possesses a Leucine Zipper domain, E6 binding consensus motif and a Ca binding EF-hand motif. DBC-1 bound with both low risk type E6, type 11, and with high risk E6s, type 16 and 18, but the binding with low risk 11E6 was weaker than with high risk 16 and 18E6. We also revealed that E6 oncoprotein degrades DBC-1 in the presence of E6AP. DBC-1 localized in nucleus, but concentrated on mitochondria during apoptosis.
Our data suggest the possibility that degradation of DBC-1 by E6-E6AP might have some effect on the apoptotic signal pathway in mitochondria, which takes part in the cervical carcinogenesis Less
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Research Products
(13 results)
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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 Ia, G1 adenocarcinoma of the endometrium2007
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: 112-122
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 E6.2006
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: 501-507
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, Matsumoto Y, Nakagawa K, Minaguchi T, Oda K, Hiraike-Wada O, Ooishi H, Matsumoto K, Yasugi T, Taketani Y
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Journal Title
Genes to Cells
Pages: 453-464
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: 1217-1225
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha2005
Author(s)
Wada-Hiraike O, Yano T, Nei T, Matsumoto Y, Nagasaka K, Takizawa S, Oishi H, Arimoto T, Nakagawa S, Yasugi T, Kato S, Taketani Y.
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Journal Title
Br J Cancer 92(12)
Pages: 2286-2291
Description
「研究成果報告書概要(欧文)」より
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[Book] Canaer Sci2006
Author(s)
Nagasaka K, Nakagawa S, Yano T, Takizawa S
Total Pages
1217-1225
Publisher
Human homolog Drosophila tumor suppressor scribble nagatively negatively regulates cell-cycle progression from GI to Sphase by localizing at the basolateral membrane in epithelial cells
Description
「研究成果報告書概要(和文)」より
