ESX: A structurally unique Ets overexpressed early during human breast tumorigenesis
ESX: A structurally unique Ets overexpressed early during human breast tumorigenesis
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DOI：
10.1038/sj.onc.1200978
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发表时间：
1997-04-03
期刊：
影响因子：
8
通讯作者：
Benz, CC
中科院分区：
文献类型：
--
作者：
Chang, CH;Scott, GK;Benz, CC
转录调控因子-gt；30是ETS多基因转录调控家族中的已知成员，它们参与早期胚胎发育和晚期组织成熟，指导特定阶段和组织受限的靶基因表达程序，因此越来越受到认可。ETS基因主要通过其85个氨基酸的ETS DNA结合域进行识别，并分布在所有后生动物谱系中，形成不同的亚家族。当ETS基因过度表达或重排成保留ETS结构域的嵌合体时，也会在人类和其他脊椎动物中产生恶性肿瘤，这表明它们的致癌潜力由它们调控的靶基因的程序决定。为了寻找调控HER2/neu(c-erb B2)癌基因表达的Ets因子，我们发现了一个新的上皮限制性Ets，编码与果蝇E74/人Elf-1亚家族同源的Ets结构域，与远亲Ets-L亚家族同源的氨基末端区域(A区或点状区)，以及与淋巴细胞限制性高迁移组(HMG)蛋白SOX4的反式激活域同源的富丝氨酸框。ESX编码的重组蛋白(用于丝氨酸盒上皮限制)在凝胶迁移率改变分析中显示出ETS样的DNA结合特异性，并在瞬时转染实验中反式激活ETS反应的启动子元件，包括在HER2/neu癌基因中发现的元件。ESX位于染色体1q32上，该区域在50%的早期乳腺癌中被扩增，是HER2/neu激活的乳腺癌细胞中HER2/neu高表达的。组织杂交表明ESX在人类乳腺癌发展的早期阶段变得过表达，称为导管原位癌(DCIS)。
The >30 known members of the Ets multigene family of transcriptional regulators are increasingly being recognized for their involvement in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of target gene expression. Identifiable primarily by their 85 amino acid ETS DNA-binding domain and dispersed across all metazoan lineages into distinct subfamilies, Ets genes also produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain, suggesting that their oncogenic potential is determined by the program of target genes they regulate. Searching for Ets factors that regulate expression of the HER2/neu (c-erbB2) oncogene in human breast cancer, we identified a new epithelium-restricted Ets encoding an ETS domain homologous to the Drosophila E74/human Elf-1 subfamily, an amino-terminal region (A-region or Pointed domain) homologous to the distantly related Ets-l subfamily, and a serine-rich box homologous to the transactivating domain of the lymphocyte-restricted High Mobility Group (HMG) protein, SOX4. Recombinant protein encoded by ESX (for epithelial-restricted with serine box) exhibits Ets-like DNA binding specificity in electrophoretic mobility shift assays and, in transient transfection assays, transactivates Ets-responsive promoter elements including that found in the HER2/neu oncogene. ESX is located at chromosome 1q32 in a region known to be amplified in 50% of early breast cancers, is heregulin-inducible and overexpressed in HER2/neu activated breast cancer cells. Tissue hybridization suggests that ESX becomes overexpressed at an early stage of human breast cancer development known as ductal carcinoma in situ (DCIS).