| Project/Area Number |
14571541
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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, Research Associate, 医学部附属病院, 助手 (70270874)
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| Co-Investigator(Kenkyū-buntansha) |
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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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Tumor suppressor / human scribble / cervical cancer / human papillomavirus / E6 oncoprotein / intracellular localization / 結合蛋白同定 / 細胞内局在 |
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| Research Abstract |
Recently, a LAP protein. Scribble, was Identified in Drosophlla epithelia as a basolateral protein that controls the apical-basolateral polarity. Loss of Scribble causes disorganization and overgrowth of the epithelia. Scribble has a human homologue, human Scribble (hScrib). Which is a substrate of ubiquikin-mediated degradation by human papillomavirus E6 and the E6AP ubiquitin-protein Iigase. In the present study. we revcated that hScrib localized to the basolateral regions of the opithelial cell line MDCK and human utorine cervical opithelial tissues by immunoflorescence. Human Scribble co-localied rather with the adherens junction protein E-cadherin, but not with the right junction protein ZO-1. Histochemical analysis showed a dramatic decrense in the expression of hScrib with the progression of disease from normal terine carvical *issues to invasive cervical cancers through the precursor losious. In contrast, the expression of hScrib was retained in the throughout upithelial tayer of tthe HPV-negative cervical high-grade squamous intracpithelial lesions. Although quantitative RT-RCR reveated no signicant down-regulation of human scribble mRNA expresion in the high-grade squamous intracpithelial losions, it reveated a cleardown-regulation in the invasive cancers. These results suggest the possibility that degradation by HPV E6 is one of causal role for the progressive decrease of hAcrib expression during the disease progression from low-grade squamous intraopithelial lesions to high-grade squamousintracpithelial losions and a cooperative role of down-regulation of human scribble mRNA expression and ubiquitin-mediated degradation of hScrib by E6 and E6AP lead to the complete decrease of hScrib expression during the process of carcinogenesis from H-SIL to invasive cancer. These data underscore the Importance of hScrib in the construction of tissue architecture and prevention of cancer development.
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