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

点击翻译按钮获取中文摘要

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.