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

2003 Fiscal Year Final Research Report Summary

• Project/Area Number: 14570114
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: RIKEN (The Institute of Physical and Chemical Research)
• Principal Investigator: MAEKAWA Toshio RIKEN (The Institute of Physical and Chemical Research), Lab. of Molec. Genet., Senior Scientist, 分子遺伝学研究室, 副主任研究員 (90201764)
• Project Period (FY): 2002 – 2003
• Keywords: ATF-2 / mammary tumor / DNA chip / hypoxia / GADD45α / apoptosis / knockout mouse / BRCA1

Research Abstract

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.