Expression and patho-physiological function of cystine transporter

胱氨酸转运蛋白的表达及其病理生理功能

• 批准号: 13470031
• 负责人: BANNAI Shiro
• 金额: $ 8.9万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470031/
• 关键词: 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

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 follows1.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 fluid2.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 level3.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 Nrf24.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 ATF45.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

转运系统x_c^-介导细胞外胱氨酸与细胞内谷氨酸的交换转运。该系统由xCT和4F 2 hc两种蛋白质组成，前者被认为是实际的转运蛋白。本课题研究了xCT基因在某些细胞和组织中的表达和转录调控，并试图通过构建xCT基因敲除小鼠来阐明xc ^-系统在整个小鼠中的病理生理作用。结果表明：1. xCT基因在脑膜和脑室周围器官中有较强的表达。例如，在一个实施例中，最后区和穹窿下器。这可能表明系统x-1有助于维持氧化还原状态（即，2.系统x_c^-在人卵巢癌顺铂耐药细胞株中的表达高于顺铂敏感细胞株。发现x_c^-系统通过增加谷胱甘肽水平而对顺铂耐药起作用。我们发现在xCT基因的5 '侧翼区存在几个亲电反应元件，亲电试剂通过这些元件中的一个与转录因子Nrf 24结合来转录诱导xCT。我们研究了胱氨酸剥夺诱导x_c^-系统的机制。我们发现xCT基因的S '侧翼区存在两个氨基酸反应元件，通过这两个元件与转录因子ATF 45联合作用，使xCT基因被胱氨酸剥夺而转录诱导。目前，这些小鼠出生后3个月，表面上是正常的，表型分析仍有待研究

项目成果

Suzuka Okuno: "Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines."British Journal of Cancer. 88. 951-956 (2003)

Suzuka Okuno：“胱氨酸转运对人卵巢癌细胞系细胞内谷胱甘肽水平和顺铂耐药性的作用。”英国癌症杂志。

Hideyo Sato: "Distribution of cystine/glutamate exchange transporter, system x_c^-, in the mouse brain"The Journal of Neuroscience. 22・18. 8028-8033 (2002)

佐藤英世：“小鼠大脑中胱氨酸/谷氨酸交换转运蛋白系统 x_c^- 的分布”《神经科学杂志》22・18（2002 年）。

Hideyo Sato: "Effect of oxygen on induction of the cystine transporter by bacterial LPS in mouse peritoneal macrophages."Journal of Biological Chemistry. 276・13. 10407-10412 (2001)

佐藤英世：“氧气对小鼠腹腔巨噬细胞中细菌 LPS 诱导胱氨酸转运蛋白的影响”，生物化学杂志 276・13（2001）。

Hideyo Sato, et al.: "Distribution of cystine/glutamate exchange transporter, system x_c^-, in the mouse brain"Journal of Neuroscience. 22(18). 8028-8033 (2002)

Hideyo Sato 等人：“小鼠大脑中胱氨酸/谷氨酸交换转运蛋白系统 x_c^- 的分布”神经科学杂志。

Kazumi Kuriyama-Matsumura: "Effects of hyperoxia and iron regulatory protein-1 activity and the ferritin synthesis in mouse macrophages"Biochimica et Biophysica Acta. 1544. 370-377 (2001)

Kazumi Kuriyama-Matsumura：“高氧和铁调节蛋白 1 活性以及小鼠巨噬细胞中铁蛋白合成的影响”生物化学和生物物理学学报。