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

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.
Mesh Terms:
Activating Transcription Factor 2, Animals, BRCA1 Protein, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, Male, Mammary Neoplasms, Experimental, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Mice, Mutant Strains, Nuclear Proteins, Serpins, Tumor Suppressor Protein p53
Oncogene
Date: Feb. 14, 2008
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