2004 Fiscal Year Final Research Report Summary
Analysis of a role of r-and K-selection during malignant progression and K-induced multidrug resistance
| Project/Area Number |
15590995
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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 | The University of Tokyo |
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Principal Investigator |
MOTOKURA Toru The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (00192823)
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| Project Period (FY) |
2003 – 2004
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| Keywords | multistep tumorigenesis / natural selection / P-glycoprotein / drug resistance / Myc / Ras / 14-3-3 / DNA methylation |
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| Research Abstract |
We examined the underlying mechanisms behind the emergence of multidrug resistance (MDR) phenotype after K-selection of c-myc-and EJ-ras-transformed rat embryo fibroblasts (REFS). The MDR was partly related to the overexpression of p-glycoprotein/MDR1, which was at least partly attributed to the upregulated expression of nuclear transcription factor Y α. We also found the involvement of other mechanisms such as reduced cell proliferation, suppressed expression of equilibrative nucleoside transporter 1 and upregulated expression of cytidine deaminase. Each of these mechanisms is reported in the in vivo human tumors and the model may recapitulate the development of MDR in human tumors. In addition, we cloned 14-3-3σ cDNA from K-selected cells as a target of K-selection. The 14-3-3σ gene was hypermethylated after r-selection and thus the expression was suppressed. On the contrary, the 5'-region of the gene was completely demethylated after K-selection and the expression levels increased dramatically. We observed the plasticity of DNA methylation as well as its irreversibility. The in vitro model of genetic tumorigenesis with c-myc-and EJ-ras-transformed REFs turned out to be an interesting model for study of epigenetics in cancer development.
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