Regulation of Id1 expression by Src: Implications for targeting of the bone morphogenetic protein pathway in cancer
Regulation of Id1 expression by Src: Implications for targeting of the bone morphogenetic protein pathway in cancer
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DOI：
10.1158/0008-5472.can-07-6403
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发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
Kung, Hsing-Jien
中科院分区：
文献类型：
--
作者：
Gautschi, Oliver;Tepper, Clifford G.;Kung, Hsing-Jien
Src酪氨酸激酶激活失调和Id 1表达升高是侵袭性肿瘤生物学的独立介质。本报告暗示Src信号转导作为Id 1基因表达的关键调节因子。微阵列分析显示，Id家族基因是A549肺癌细胞与小分子Src抑制剂AZD 0530孵育后下调最多的基因之一。Id 1转录和蛋白水平以剂量依赖性方式有效降低，同时降低活化Src水平。这些作用在一组肺癌、乳腺癌、前列腺癌和结肠癌细胞系中是保守的，并通过PP 2、Src siRNA和Src阻断肽抑制Id 1表达的能力得到证实。PP 2，AZD 0530，和显性负性Src废除Id 1启动子活性，这是由组成型活性Src诱导。Id 1启动子的Src响应区定位于翻译起始位点上游1，199至1，360 bp的区域，并含有Smad结合元件。Src也需要骨形态发生蛋白-2（BMP-2）诱导的Id 1表达和启动子活性，被BMP 2适度激活，并与Smad 1/5复合。相反，Src抑制剂阻断Smad 1/5核转位和与Id 1启动子的Src反应区结合。与Src和Id 1在癌细胞侵袭中的作用一致，Src抑制剂和141 siRNA降低了癌细胞侵袭，而Id 1过表达增加了癌细胞侵袭。综上所述，这些结果表明Src与BMP-Smad-Id通路积极相互作用，并为Id 1的靶向抑制提供了新的途径。
Deregulated activation of the Src tyrosine kinase and heightened Id1 expression are independent mediators of aggressive tumor biology. The present report implicates Src signaling as a critical regulator of Id1 gene expression. Microarray analyses showed that Id family genes were among the most highly down-regulated by incubation of A549 lung carcinoma cells with the small-molecule Src inhibitor AZD0530. Id1 transcript and protein levels were potently reduced in a dose-dependent manner concomitantly with the reduction of activated Src levels. These effects were conserved across a panel of lung, breast, prostate, and colon cancer cell lines and confirmed by the ability of PP2, Src siRNA, and Src-blocking peptides to suppress Id1 expression. PP2, AZD0530, and dominant-negative Src abrogated Id1 promoter activity, which was induced by constitutively active Src. The Src-responsive region of the Id1 promoter was mapped to a region 1,199 to 1,360 bps upstream of the translation start site and contained a Smad-binding element. Src was also required for bone morphogenetic protein-2 (BMP-2)-induced Id1 expression and promoter activity, was moderately activated by BMP2, and complexed with Smad1/5. Conversely, Src inhibitors blocked Smad1/5 nuclear translocation and binding to the Src-responsive region of the Id1 promoter. Consistent with a role for Src and Id1 in cancer cell invasion, Src inhibitors and 141 siRNA decreased cancer cell invasion, which was increased by Id1 overexpression. Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1.