Analysis of the inhibitory mechanisms of IFN gamma induced gene expression by hypoxia

缺氧抑制IFNγ诱导基因表达的机制分析

• 批准号: 22791797
• 负责人: HIROI Miki
• 金额: $ 3.33万
• 依托单位: Meikai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22791797/
• 关键词: シグナル伝達; 低酸素; インターフェロン; ケモカイン; 遺伝子制御

We have previously shown that hypoxia down-regulated the IFN-induced expression of chemokine CXCL9 and CXCL10 genes in human tumor cell lines. We have explored the mechanisms by which hypoxia down-regulates the IFN-induced gene expressions and found that although HIF-1 was not involved in the transcriptional repression of the IFN-induced genes, recruitments of Pol II, coactivator SRC-1 were inhibited under the hypoxia. In this study, we investigated potential involvements of HIF-2, histone methylation at the promoter region of the CXCL9 genes, and mediator complex that participates in the recruitment of Pol II for the hypoxia-mediated transcriptional repression. Over expression of an active form of HIF-2 in HEK293 cells inhibited the CXCL9 promoter activity, suggesting that HIF-2 negatively regulates CXCL9 expression. Real-time RT-PCR analysis showed that constitutive expressions of mRNAs for methyltransferase and members of mediator complex were observed in HSC-2 cells.

我们之前的研究表明，缺氧可下调ifn诱导的趋化因子CXCL9和CXCL10基因在人肿瘤细胞系中的表达。我们探索了缺氧下调ifn诱导基因表达的机制，发现尽管HIF-1不参与ifn诱导基因的转录抑制，但在缺氧条件下，Pol II和辅激活因子SRC-1的募集受到抑制。在这项研究中，我们研究了HIF-2、CXCL9基因启动子区域组蛋白甲基化以及参与Pol II募集的中介复合物在缺氧介导的转录抑制中的潜在作用。HEK293细胞中过表达一种活性形式的HIF-2可抑制CXCL9启动子活性，表明HIF-2负性调节CXCL9的表达。实时RT-PCR分析显示，HSC-2细胞中甲基转移酶和中介复合物成员mrna的组成性表达。

项目成果

低酸素はIFNγ誘導性ケモカインCXCL9/Mig、CXCL10/IP-10の発現を抑制する

缺氧抑制 IFNγ 诱导的趋化因子 CXCL9/Mig 和 CXCL10/IP-10 的表达

• 发表时间: 2010
• 作者: 廣井美紀;大森喜弘
• 通讯作者: 大森喜弘