ATF-2 controls transcription of Maspin and GADD45α genes independently from p53 to suppress mammary tumors
ATF-2 controls transcription of Maspin and GADD45α genes independently from p53 to suppress mammary tumors
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DOI：
10.1038/sj.onc.1210727
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发表时间：
2008-02-14
期刊：
影响因子：
8
通讯作者：
Ishii, S.
中科院分区：
文献类型：
--
作者：
Maekawa, T.;Sano, Y.;Ishii, S.
激活转录因子ATF-2是p38和JNK的靶点，参与应激诱导的细胞凋亡。ATF-2杂合突变(ATF-2(+/-))小鼠极易发生乳腺肿瘤。凋亡调控基因GADD45α和乳腺癌抑制基因Maspin在ATF-2(+/-)小鼠乳腺肿瘤中表达下调，这两个基因都是已知的P53靶基因。在这里，我们分析了ATF-2如何控制GADD45a和Maspin的转录。ATF-2和P53独立激活GADD45a转录。ATF-2不直接与GADD45a启动子结合，而是通过Oct-1和NF-I招募。ATF-2同时与Oct-1、NF-I和乳腺癌抑制基因BRCA1结合，激活转录。关于Maspin，ATF-2和P53直接结合到Maspin启动子的不同位置，独立地激活其转录。与ATF-2和P53独立激活Maspin和GADD45a转录的观察一致的是，P53的一个副本的丢失缩短了ATF-2(+/-)小鼠乳腺肿瘤的发生时间。这些研究表明，ATF-2与两个肿瘤抑制基因BRCA1和P53之间存在功能联系。
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 GADD45 alpha 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 GADD45a and Maspin. ATF-2 and p53 independently activate the GADD45a transcription. ATF-2 does not directly bind to the GADD45a 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 GADD45a 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.