Functional analysis of ATF-2 gene family members by using gene knockout mouse

利用基因敲除小鼠对ATF-2基因家族成员进行功能分析

• 批准号: 14570114
• 负责人: MAEKAWA Toshio
• 金额: $ 2.24万
• 依托单位: RIKEN (The Institute of Physical and Chemical Research)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570114/
• 关键词: ATF-2; mammary tumor; DNA chip; hypoxia; GADD45α; apoptosis; knockout mouse; BRCA1; Maspin; 低酸素(ハイポキシア); 転写因子; GADD45α; アニソマイシン

Transcription factor ATF-2 is a nuclear target of stress-activated protein kinases (SAPKs), which is involved in stress-induced apoptosis. Here I report that Atf-2 heterozygous mutant mice are highly prone to spontaneous formation of certain types of mammary tumours including scirrhous adenocarcinoma. The level of ATF-2 mRNA is also reduced in similar types of human breast cancers. The Atf-2-deficient mouse embryonic fibroblasts are more resistant to the hypoxia-induced apoptosis than wild-type cells, and cannot induce Gadd45α gene expression in response to hypoxia and anisomycin. The Gadd45α mRNA levels are also reduced in mammary tumors of Atf-2 heterozygous mice.ATF-2 forms a complex with BRCA1,the most common tumour suppressor of breast cancers, and is recruited to the GADD45α promoter via two transcription factors Oct-1 and NF-I to activate the GADD45α gene transcription. Thus, AFT-2 acts as a tumor suppressor of certain types of breast cancers by inducing GADD45α transcription with BRCA1 in response to hypoxia stress.

转录因子ATF-2是应激激活蛋白激酶（SAPKs）的核靶点，参与应激诱导的细胞凋亡。在这里，我报告，Atf-2杂合子突变小鼠是非常容易自发形成某些类型的乳腺肿瘤，包括硬癌。ATF-2 mRNA的水平在类似类型的人类乳腺癌中也降低。Atf-2缺陷型小鼠胚胎成纤维细胞对缺氧诱导的细胞凋亡具有较强的耐受性，且不能诱导Gadd 45 α基因表达。ATF-2与乳腺癌最常见的肿瘤抑制因子BRCA 1形成复合物，通过两个转录因子Oct-1和NF-1募集到GADD 45 α启动子，激活GADD 45 α基因转录。因此，AFT-2作为某些类型的乳腺癌的肿瘤抑制因子，通过诱导GADD 45 α与BRCA 1的转录来响应缺氧应激。