| Project/Area Number |
18591042
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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 |
Hematology
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| Research Institution | Tottori University (2007)
The University of Tokyo (2006) |
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Principal Investigator |
MOTOKURA Toru Tottori University, Faculty of Medicine, Associate Professor (00192823)
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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 |
¥3,870,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥270,000)
Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2006: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | Gene / virus / malignancy / natural selection / disease model |
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| Research Abstract |
We reported the emergence of multidrug resistant clones over-expressing P-glycoprotein under K-selection (confluent culture) using c-myc- and EJ-ras-transformed rat embryo fibroblasts (REF). Using this REF tumor model, we identified 14-3-3σ as a gene involved in the clonal evolution under K-selection. The 14-3-3σ gene is primarily expressed in epithelial cells and is frequently involved in solid tumors of epithelial origin by gene silencing via DNA methylation. In the REF tumor model, the 14-3-3σ gene was hypermethylated after γ-selection (sparse culture) and the expression was suppressed while the gene was completely demethylated after K-selection and the expression levels increased dramatically. Then we examined the expression and DNA methylation status of the 14-3-3σ gene in 41 hematological cell lines and 129 patients with hematological malignancies. The expression levels were extremely low in normal blood cells as well as in almost all hematological cell lines. However, we found the over-expression of the 14-3-3σ gene in a subset of mature lymphoid malignancies suggesting the presence of K-selection in clonal evolution in vivo.
In addition, we attempted to generate a human model of EBV-associated lymphoproliferative disorders (EBV-LPD) by using EBV-infected lymphoblastoid cell lines (LCL) and an EBV-based vector. We found cells which had been transduced with the hTERT expression plasmid proliferated and were retained in culture for a long period of time and that even monoclonal evolution with chromosomal aberration developed in vitro. Thus the comparison between human EBV-LPD and the LCL model warrants further analysis.
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