HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor β inhibitor Smad7 via the ETS protein ER81
HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor β inhibitor Smad7 via the ETS protein ER81
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DOI：
10.1074/jbc.m307202200
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发表时间：
2003-11-07
影响因子：
4.8
通讯作者：
Janknecht, R
中科院分区：
文献类型：
--
作者：
Dowdy, SC;Mariani, A;Janknecht, R
细胞因子转化生长因子β（TGF-β）通过阻断细胞周期进程在预防肿瘤形成中起重要作用。因此，许多癌症表现出TGF-β信号传导组分的突变或TGF-β途径抑制剂如Smad 7的表达增强。在这份报告中，我们表明，癌蛋白HER 2/Neu能够与ETS转录因子ER 81合作，激活Smad 7在乳腺癌，子宫内膜癌和卵巢癌细胞系的转录。ER 81结合Smad 7启动子内的两个ETS位点，并且这些ETS位点之一的突变大大降低了HER 2/Neu和ER 81对Smad 7的诱导。此外，我们发现Smad 7激活涉及通过ERK丝裂原活化蛋白激酶途径从HER 2/Neu到ER 81的信号处理。因此，我们已经发现了一种新的机制，致癌HER 2/Neu与ER 81合作，可以通过Smad 7上调诱导致癌作用。此外，我们表明，TAK 1，TGF-β-活化的蛋白激酶，刺激ER 81通过p38丝裂原活化蛋白激酶途径，从而诱导Smad 7启动子。这表明通过激活Smad 7转录来减弱TGF-β信号传导不仅可以通过TGF-β受体调节的Smad蛋白进行，还可以通过涉及ER 81和TAK 1的独立途径进行。
The cytokine transforming growth factor beta (TGF-beta) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-beta signaling components or enhanced expression of inhibitors of the TGF-beta pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 upregulation. Moreover, we show that TAK1, a TGF-beta-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-beta signaling by activating Smad7 transcription may proceed not only through TGF-beta receptor-regulated Smad proteins but also through an independent pathway involving ER81 and TAK1.