| Project/Area Number |
13671348
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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 |
Digestive surgery
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| Research Institution | TOHO UNIVERSITY |
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Principal Investigator |
HEMMI Hiromichi Toho Univ Sch Med, Dept Mol Biol, Associate Professor, 医学部, 助教授 (90165514)
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| Co-Investigator(Kenkyū-buntansha) |
ARITA Michitsune Toho Univ Sch Med, Dept Mol Biol, Research Associate, 医学部, 助手 (80307719)
小池 淳一 東邦大学, 医学部, 助手 (30339155)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | DNA mismatch repair genes / hMLH1 gene / hMSH2 gene / histone / acetylation / transcription factor / colorectal cancer / cell lines / ミスマッチ修復遺伝子 / ヒストンH4 / 転写活性 / アセチル化状態 |
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| Research Abstract |
Accumulation of mutations in oncogenes and tumor suppressor genes is essential for generation of colorectal cancer. Defect of a DNA mismatch repair (MMR) gene is known to be responding to one of the accumulated mutations in these cancer-related genes. Seven human MMR genes including hMLH1 and hMSH2 have been identified. More than half of most HNPCC and certain fraction of sporadic colorectal cancers shows abnormality in the hMLH1 and hMSH2 genes. An epigeneic modification, namely hypermethylation, in the promoter region of the hMLH1 gene has been demonstrated as one of mechanisms of gene inactivation. Since we had inactivated sporadic cases without mutation in the gene nor hypermethylation, we looked for the another mechanism of inactivation. In this study, we focused two points: one is relationship between histone acetylation status and expression of hMLH1 and hMSH2; second is a regulatory mechanism of the hMLH1 gene expression.
1) Acetylation status of the hMLH1 gene promoter in human colorectal cancer cell lines was examined by a ChIP method using anti histone H4 antibody. There was no correlation between protein expression and the acetylation status. However, TSA, an inhibitor of the deacetylation enhanced gene expression, indicating that acetylation enhances the expression.
2) Essential sites in the promoter region of the hMLH1 gene for transcription has been identified. Then, we screened factors binding to the one of the essential sites by a yeast one-hybrid system. As on candidate, p29 protein, of which gene located in 1p31-32 where known to be frequent loss in colorectal cancer, has been found. The detailed investigation for the role and function of p29 are required in future.
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