ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors.

Abstract:

:The activating transcription factor, ATF-2, is a target of p38 and JNK that are involved in stress-induced apoptosis. Heterozygous Atf-2 mutant (Atf-2+/-) mice are highly prone to mammary tumors. The apoptosis-regulated gene GADD45alpha and the breast cancer suppressor gene Maspin, both of which are known to be p53 target genes, are downregulated in the mammary tumors arisen in Atf-2+/- mice. Here, we have analysed how ATF-2 controls the transcription of GADD45alpha and Maspin. ATF-2 and p53 independently activate the GADD45alpha transcription. ATF-2 does not directly bind to the GADD45alpha promoter; instead, it is recruited via Oct-1 and NF-I. ATF-2 simultaneously binds to Oct-1, NF-I and breast cancer suppressor BRCA1 to activate transcription. With regard to Maspin, ATF-2 and p53 directly bind to different sites in the Maspin promoter to independently activate its transcription. Consistent with the observation that ATF-2 and p53 independently activate the transcription of Maspin and GADD45alpha is that the loss of one copy of p53 shortened the period required for mammary tumor development in Atf-2+/- mice. These studies suggest the functional link between the ATF-2 and the two tumor suppressors BRCA1 and p53.

journal_name

Oncogene

journal_title

Oncogene

authors

Maekawa T,Sano Y,Shinagawa T,Rahman Z,Sakuma T,Nomura S,Licht JD,Ishii S

doi

10.1038/sj.onc.1210727

subject

Has Abstract

pub_date

2008-02-14 00:00:00

pages

1045-54

issue

8

eissn

0950-9232

issn

1476-5594

pii

1210727

journal_volume

27

pub_type

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