P53 regulates FAK expression in human tumor cells
P53 regulates FAK expression in human tumor cells
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DOI：
10.1002/mc.20395
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发表时间：
2008-05-01
影响因子：
4.6
通讯作者：
Cance, William G.
中科院分区：
文献类型：
--
作者：
Golubovskaya, Vita M.;Finch, Richard;Cance, William G.
p53蛋白的衰减是人类肿瘤中最常见的异常之一。肿瘤发生的另一个重要标志物是粘着斑激酶（FAK），一种125 kDa的酪氨酸激酶，在多种人类肿瘤中在mRNA和蛋白质水平上过表达。FAK是粘附、运动、转移和存活信号传导的关键调节剂。我们已经表征了FAK启动子，并证明p53可以抑制FAK启动子的活性在体外。在本研究中，我们发现，p53可以结合FAK启动子染色质区域在体内染色质免疫沉淀（ChIP）测定。此外，我们证明下调FAK的mRNA和蛋白水平的腺病毒过表达的p53。我们将在p53的DNA结合结构域中具有不同突变（R175 H、p53 R248 W和R273 H）的质粒引入HCT p53（-/-）细胞中，并且显示这些p53突变不结合FAK启动子并且不抑制FAK启动子活性，不像野生型p53。我们分析了原发性乳腺癌和结肠癌的p53突变和FAK表达，结果表明，与野生型p53肿瘤相比，含有p53突变的肿瘤中FAK表达增加。此外，DNA结合结构域（R282，R249和V173）中的肿瘤源性错义突变也导致FAK启动子活性增加。因此，目前的数据表明，p53可以调节FAK的表达在肿瘤发生。(c)2007 Wiley-Liss，Inc.
Attenuation of the p53 protein is one of the most common abnormalities in human tumors. Another important marker of tumorigenesis is focal adhesion kinase (FAK), a 125-kDa tyrosine kinase that is overexpressed at the mRNA and protein levels in a variety of human tumors. FAK is a critical regulator of adhesion, motility, metastasis, and survival signaling. We have characterized the FAK promoter and demonstrated that p53 can inhibit the FAK promoter activity in vitro. In the present study, we showed that p53 can bind the FAK promoter-chromatin region in vivo by chromatin immunoprecipitation (ChIP) assay. Furthermore, we demonstrated down-regulation of FAK mRNA and protein levels by adenoviral overexpression of p53. We introduced plasmids with different mutations in the DNA-binding domain of p53 (R175H, p53 R248W and R273H) into HCTp53(-/-) cells and showed that these mutations of p53 did not bind FAK promoter and did not inhibit FAK promoter activity, unlike wild type p53. We analyzed primary breast and colon cancers for p53 mutations and FAK expression, and showed that FAK expression was increased in tumors containing mutations of p53 compared to tumors with wild type p53. In addition, tumor-derived missense mutations in the DNA-binding domain (R282, R249, and V173) also led to increased FAK promoter activity. Thus, the present data show that p53 can regulate FAK expression during tumorigenesis. (c) 2007 Wiley-Liss, Inc.