Grant-in-Aid for Scientific Research on Priority Areas
|Allocation Type||Single-year Grants |
|Research Institution||KYOTO UNIVERSITY |
TSUKITA Shoichiro Kyoto University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (50155347)
FURUSE Mikio Kyoto University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90281089)
KUBO Akiharu Kyoto University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70335256)
ADACHI Makoto Kyoto University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30335244)
TSUKITA Sachiko Kyoto University, Faculty of Medicine, Professor, 医学部, 教授 (00188517)
佐々木 博之 東京慈恵会医科大学, DNA研究所, 講師 (60170693)
伊藤 雅彦 京都大学, 医学研究科, 助手 (70270486)
米村 重信 京都大学, 医学研究科, 講師 (60192811)
永渕 昭良 熊本大学, 発生医学研究センター, 教授 (80218023)
|Project Period (FY)
2000 – 2004
Completed (Fiscal Year 2004)
|Budget Amount *help
¥443,900,000 (Direct Cost: ¥443,900,000)
Fiscal Year 2004: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2003: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2002: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2001: ¥89,000,000 (Direct Cost: ¥89,000,000)
Fiscal Year 2000: ¥86,400,000 (Direct Cost: ¥86,400,000)
|Keywords||cell-cell adhesion / tight junction / claudin / occludin / ERM proteins / epidermal barrier / knockout mouse / cell proliferation / Snail / ZO-1 / ZO-2 / がん / 上皮間葉転換 / 転移浸潤 / GFP / ドラッグデリバリー / ノックアウト / 上皮細胞 / 血液脳関門 / メルリン / MUPP1 / PDZドメイン / 大腸癌 / ラディキシン / α-カテニン / β-カテニン / ERM / アドヘレンスジャンクション / カドヘリン|
More than 90% of malignant tumors are derived from the epithelium. Thus, in this project, we focused on the analyses of tight junctions and ERM proteins to clarify the nature of the. epithelium. Major results are as follows:
1. Claudin-1-deficient mice were generated. Their epidermal barrier was affected, and the proliferation of epidermal cells appeared to be abnormal.
2. Claudin-5-deficient mice were generated. Their blood-brain barrier was affected in a size-dependent manner. This finding was intriguing from the viewpoint of drug deliver to the brain tumors.
3. The dynamic behavior of claudin-based tight junction strands was successfully observed in live cells. Their behavior was more dynamic than ever expected.
4. Snail, a transcription factor, plays a key role in the epithelial-mesenchymal transition, which is important in the metastasis of cancer cells. We found that Snail completely repressed the transcription of occludin and claudins through its direct binding to the E-boxes of the promoter regions of these genes.
5. Claudin-1 was shown to be overexpressed in human colon cancer (in collaboration with Prof. Nakamura's group).
6. We established the system, in which a certain gene can be double-knocked out in cultured epithelial cells. With this system, an epithelial cell line lacking the expression of ZO-1 and ZO-2 was established.
7. The structure of the gene product of NF2, an ERM-like tumor suppressor gene, was clarified by X-ray diffraction analyses (in collaboration with Prof.Hakozaki's group).