Maekawa T, Sano Y, Shinagawa T, Rahman Z, Sakuma T, Nomura S, Licht J D, Ishii S
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, Koyadai, Tsukuba, Ibaraki, Japan.
Oncogene. 2008 Feb 14;27(8):1045-54. doi: 10.1038/sj.onc.1210727. Epub 2007 Aug 13.
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.
激活转录因子ATF-2是参与应激诱导凋亡的p38和JNK的作用靶点。杂合子Atf-2突变体（Atf-2+/-）小鼠极易患乳腺肿瘤。凋亡调节基因GADD45α和乳腺癌抑制基因Maspin，这两个基因都是已知的p53靶基因，在Atf-2+/-小鼠发生的乳腺肿瘤中表达下调。在此，我们分析了ATF-2如何控制GADD45α和Maspin的转录。ATF-2和p53独立激活GADD45α的转录。ATF-2不直接与GADD45α启动子结合；相反，它是通过Oct-1和NF-I被招募的。ATF-2同时与Oct-1、NF-I和乳腺癌抑制因子BRCA1结合以激活转录。关于Maspin，ATF-2和p53直接结合到Maspin启动子的不同位点以独立激活其转录。与ATF-2和p53独立激活Maspin和GADD45α转录的观察结果一致的是，p53一个拷贝的缺失缩短了Atf-2+/-小鼠乳腺肿瘤发生所需的时间。这些研究表明了ATF-2与两种肿瘤抑制因子BRCA1和p53之间的功能联系。
