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

转录因子ATF-2是应激激活蛋白激酶(SAPKs)的核靶标，参与应激诱导的细胞凋亡。在这里，我报告ATF-2杂合突变小鼠非常容易自发形成某些类型的乳腺肿瘤，包括硬化腺癌。在类似类型的人类乳腺癌中，ATF-2mRNA的水平也降低了。与野生型细胞相比，ATF2基因缺陷的小鼠胚胎成纤维细胞对低氧诱导的细胞凋亡具有更强的抵抗力，并且不能诱导GADD45α基因的表达。ATF-2与乳腺癌最常见的抑癌基因α形成复合体，并通过两个转录因子OCT-1和NF-I被招募到GADD45α启动子，激活GADD45α基因转录。因此，AFT-2通过与BRCA1一起诱导GADD45α转录来响应缺氧应激，从而对某些类型的乳腺癌起到肿瘤抑制作用。

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.