Notch-1 regulates transcription of the epidermal growth factor receptor through p53
Notch-1 regulates transcription of the epidermal growth factor receptor through p53
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DOI：
10.1093/carcin/bgn079
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发表时间：
2008-05-01
期刊：
影响因子：
4.7
通讯作者：
Fine, Howard A.
中科院分区：
文献类型：
--
作者：
Purow, Benjamin W.;Sundaresan, Tilak K.;Fine, Howard A.
Notch通路在癌症的发展中起着关键作用，并且越来越多地认识到其在癌症中的重要性。我们先前证明了Notch-1及其配体在胶质瘤中的过表达，并表明它们的敲低抑制胶质瘤细胞的增殖和存活。为了阐明Notch-1在胶质瘤细胞中的下游机制，我们对转染Notch-1小干扰RNA的胶质瘤细胞进行了微阵列分析。在下调的转录物中值得注意的是表皮生长因子受体（EGFR），已知其在神经胶质瘤中过表达或扩增，并且在其他癌症中也很突出。进一步的研究证实，Notch-1抑制减少胶质瘤和其他细胞系中EGFR信使RNA（mRNA）和EGFR蛋白。用Notch-1转染增加EGFR表达。此外，我们发现EGFR和Notch-1 mRNA在原发性高级别人脑胶质瘤中的水平显著相关。随后的实验表明，EGFR启动子的激活剂p53受Notch-1调控。用p53阳性和p53缺失细胞系的实验证实，p53部分介导Notch-1对EGFR表达的影响。这些结果首次显示Notch-1上调EGFR表达，并且还证明Notch-1调节胶质瘤中的p53。这些观察结果对于理解Notch在癌症和发展中的机制具有重要意义。
The Notch pathway plays a key role in the development and is increasingly recognized for its importance in cancer. We demonstrated previously the overexpression of Notch-1 and its ligands in gliomas and showed that their knockdown inhibits glioma cell proliferation and survival. To elucidate the mechanisms downstream of Notch-1 in glioma cells, we performed microarray profiling of glioma cells transfected with Notch-1 small interfering RNA. Notable among downregulated transcripts was the epidermal growth factor receptor (EGFR), known to be overexpressed or amplified in gliomas and prominent in other cancers as well. Further studies confirmed that Notch-1 inhibition decreased EGFR messenger RNA (mRNA) and EGFR protein in glioma and other cell lines. Transfection with Notch-1 increased EGFR expression. Additionally, we found a significant correlation in levels of EGFR and Notch-1 mRNA in primary high-grade human gliomas. Subsequent experiments showed that p53, an activator of the EGFR promoter, is regulated by Notch-1. Experiments with p53-positive and -null cell lines confirmed that p53 partially mediates the effects of Notch-1 on EGFR expression. These results show for the first time that Notch-1 upregulates EGFR expression and also demonstrate Notch-1 regulation of p53 in gliomas. These observations have significant implications for understanding the mechanisms of Notch in cancer and development.