| Project/Area Number |
18390117
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Tohoku University |
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Principal Investigator |
FUKUSHIGE Shinichi Tohoku University, Tohoku University School of Medicine, Department of Molecular Pathology, Associate Professor (90192723)
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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 |
¥16,560,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥1,860,000)
Fiscal Year 2007: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Fiscal Year 2006: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Keywords | Gene / Regulation of gene expression / Transcriptional silencing / Methyl-CpG binding protein / Epigenetics |
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| Research Abstract |
Epigenetic modifications such as DNA methylation and histone modification play crucial roles in the pathogeneses of cancer by transcriptional silencing of tumor suppressor genes. To clarify the mechanism(s) in which methyl-CpG binding domain (MBD) proteins repress transcription, we analyzed proteins interacting with MBD4 and developed the methods to search cancer-related genes regulated by MBD proteins.
First, we found that Ret finger protein (RFP) interacts with MBD4 and enhances MBD2-and MBD4-dependent transcriptional repression. Because RFP has been detected at high levels in a variety of tumor cell lines as well as testis, and embryos, RFP may have an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis.
We next found that NF_KB transcriptional activation domain linked to MBD (NF_κB(AD)-MBD) reactivated the expression of densely methylated MLH1 genes in HEK293T and AN3CA cells without demethylation. This phenomenon seems to be general since we observed the transcriptional reactivation in all ten cancer-related genes analyzed so far. Furthermore, microarray analyses using HEK293T cells transfected with HF_κB(AD)-MBD showed re-expression of a variety of cancer-related genes such as CDH1. Therefore, this approach may provide an efficient method to screen epigenetically silenced cancer-related genes mediated by MBD proteins.
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