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 (SAPK) 的核靶标，参与应激诱导的细胞凋亡，在此我报告 Atf-2 杂合突变小鼠极易自发形成某些类型的乳腺肿瘤。包括硬性腺癌在内的类似类型的人类乳腺癌中，ATF-2 mRNA 水平也降低，Atf-2 缺陷的小鼠胚胎成纤维细胞对乳腺癌的抵抗力更强。 Atf-2 杂合子小鼠的乳腺肿瘤中 Gadd45α mRNA 水平也降低。ATF-2 与 BRCA1 形成复合物。乳腺癌最常见的肿瘤抑制因子，通过两个转录因子 Oct-1 和 NF-I 被招募到 GADD45α 启动子，以激活GADD45α 基因转录因此，AFT-2 通过响应缺氧应激诱导 GADD45α 转录与 BRCA1 一起充当某些类型乳腺癌的肿瘤抑制因子。