Hentges Kathryn E, Weiser Keith C, Schountz Tony, Woodward Lanette S, Morse Herbert C, Justice Monica J
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Oncogene. 2005 Feb 10;24(7):1220-30. doi: 10.1038/sj.onc.1208243.
Retroviral insertions that activate proto-oncogenes are a primary cause of tumors in certain strains of mice. The AKXD recombinant inbred mice are predisposed to a variety of leukemias and lymphomas as a result of viral integration. One common insertion site, the ecotropic viral insertion site 3 (Evi3), has been implicated in most B-cell tumors in the AKXD-27 strain. The Evi3 gene encodes a zinc-finger protein with sequence similarity to the Early B-cell Factor-Associated Zinc-finger gene (EBFAZ). We show that the Evi3 gene is overexpressed in several tumors with viral insertions at Evi3, which results in the upregulation of Early B-cell Factor (EBF)-target gene expression, suggesting that Evi3 modulates EBF activity. Reconstitution of primary leukemia cells showed that these tumors express high densities of the B-cell surface proteins CD19 and CD38, which are EBF targets. Using a transactivation assay, we show that the terminal six zinc-fingers of Evi3 are required for modification of EBF activity. This is the first evidence that Evi3 expression in tumors alters the level of EBF target genes, and the first characterization of the Evi3 protein domains required for modulation of EBF activity. Further, these data imply that Evi3 misexpression initiates tumorigenesis by perturbing B-cell development via an interaction with EBF.
激活原癌基因的逆转录病毒插入是某些品系小鼠肿瘤的主要成因。AKXD重组近交系小鼠由于病毒整合而易于患多种白血病和淋巴瘤。一个常见的插入位点，嗜亲性病毒插入位点3（Evi3），与AKXD - 27品系中的大多数B细胞肿瘤有关。Evi3基因编码一种锌指蛋白，其序列与早期B细胞因子相关锌指基因（EBFAZ）相似。我们发现Evi3基因在几个Evi3位点有病毒插入的肿瘤中过表达，这导致早期B细胞因子（EBF）靶基因表达上调，表明Evi3调节EBF活性。原代白血病细胞的重建显示，这些肿瘤表达高密度的B细胞表面蛋白CD19和CD38，它们是EBF的靶标。通过反式激活分析，我们发现Evi3的末端六个锌指对于EBF活性的修饰是必需的。这是Evi3在肿瘤中的表达改变EBF靶基因水平的首个证据，也是调节EBF活性所需的Evi3蛋白结构域的首次表征。此外，这些数据表明Evi3的错误表达通过与EBF相互作用干扰B细胞发育而引发肿瘤发生。
