Ben-Yosef T, Yanuka O, Benvenisty N
Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
Oncogene. 1996 Nov 7;13(9):1859-66.
myc oncogenes are transcription factors regulating the level of expression of other genes. Using a subtraction/coexpression strategy, a murine genetic target for Myc regulation was isolated. To further characterize this target gene, named ECA39, we have recently isolated the human, nematode and budding yeast homologs of the mouse gene. The recognition site for Myc binding, located 3' to the start site of transcription in the mouse gene, is conserved in the human homolog. Transfection experiments demonstrated that the Myc binding site of the human gene, mediates activation of a reporter gene in response to over-expression of c-myc. The activation was better executed when the c-Myc binding element was positioned downstream to the promoter, which is the usual position of the c-Myc DNA binding element in its genetic targets. The tissue specific expression of human ECA39 during embryogenesis is similar to that of the mouse homolog. Moreover, ECA39 is expressed in c-myc induced human tumors. It is expressed in Burkitt's lymphoma (where c-myc is translocated and activated) but not in non Burkitt's B-cell lymphoma or in T-cell lymphoma. Thus, it seems that ECA39 is a target for c-myc oncogenesis in humans. In yeast, where c-myc is absent, the ECA39 sequences lack the c-Myc binding element. However, the promoter region of the yeast ECA39 harbors several Gcn4 binding elements. Moreover, ECA39 is markedly down regulated in cells deleted for gcn4, and deletion of Gcn4 binding elements down regulated the transcription from ECA39 promoter. We thus suggest that ECA39 is a target for c-Myc regulation in mammals, while in yeast the regulator is not c-Myc but the c-Jun/c-Fos homolog - Gcn4.
Myc癌基因是调控其他基因表达水平的转录因子。利用消减/共表达策略，分离出了一个受Myc调控的小鼠基因靶点。为了进一步表征这个名为ECA39的靶基因，我们最近分离出了该小鼠基因的人类、线虫和芽殖酵母同源物。在小鼠基因中，位于转录起始位点3'端的Myc结合位点在人类同源物中是保守的。转染实验表明，人类基因的Myc结合位点在c-myc过表达时介导报告基因的激活。当c-Myc结合元件位于启动子下游时，激活效果更好，而这正是c-Myc DNA结合元件在其基因靶点中的通常位置。人类ECA39在胚胎发育过程中的组织特异性表达与小鼠同源物相似。此外，ECA39在c-myc诱导的人类肿瘤中表达。它在伯基特淋巴瘤（c-myc发生易位并被激活）中表达，但在非伯基特B细胞淋巴瘤或T细胞淋巴瘤中不表达。因此，似乎ECA39是人类c-myc致癌作用的一个靶点。在不存在c-myc的酵母中，ECA39序列缺乏c-Myc结合元件。然而，酵母ECA39的启动子区域含有几个Gcn4结合元件。此外，在缺失gcn4的细胞中，ECA39明显下调，而缺失Gcn4结合元件会下调ECA39启动子的转录。因此，我们认为ECA39是哺乳动物中c-Myc调控的一个靶点，而在酵母中，调控因子不是c-Myc而是c-Jun/c-Fos同源物——Gcn4。
