| Project/Area Number |
13470031
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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 |
Pathological medical chemistry
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| Research Institution | University of Tsukuba |
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Principal Investigator |
BANNAI Shiro University of Tsukuba, Institute of Basic Medical Sciences, Professor, 基礎医学系, 教授 (70019579)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Hideyo Yamagata University, Faculty of Agriculture, Associate Professor, 農学部, 助教授 (60235380)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2002: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥6,200,000 (Direct Cost: ¥6,200,000)
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| Keywords | cystine / glutathione / amino acids / transporter / redox / oxidative stress / gene expression / 酸素 / 遺伝子発現調節 / システイン / 活性酸素 |
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| Research Abstract |
Transport system x_c^-mediates the exchange transport between extracellular cystine and intracellular glutamate. This system is composed of two proteins, xCT and 4F2hc, and the former is thought to be the actual transporter. In this project we have investigated the expression and the transcriptional regulation of xCT gene in some cells and tissues and have tried to produce xCT gene-knockout mouse to elucidate the patho-physiological role of system x_c^-in whole mouse. The results are as follows
1.xCT gene was strongly expressed in meninges and some circumventricular organs, e. g., area postrema and subfornical organ. This may suggest that system x~' contributes to the maintenance of the redox state (i, e., cysteine/cystine ratio) in the cerebrospinal fluid
2.System x_c^-was highly expressed in cisplatin-resistant variant of human ovarian cancer cell lines compared with cisplatin sensitive cell lines. It was found that system x_c^-contributes to the cisplatin-resistancy by increasing glutathione level
3.We have studied the mechanism by which system x_c^-activity is induced by electrophilic agents. We found that several electrophile response elements exist in the 5'-flanking region of xCT gene and that electrophilic agents induce the xCT transciptionally via one of these elements in association with the transcription factor Nrf2
4.We have studied the mechanism by which system x_c^-is induced by cystine deprivation. We found that two amino acid response elements exist in the S'-flanking region of xCT gene and that the xCT is induced transcriptionally by cystine deprivation via these two elements in association with the transcription factor ATF4
5.xCT gene-knockout mice have been successfully produced. At present these mice, three months after birth, are apparently normal and the phenotype analysis remains to be investigated
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