Shi Yujiang, Sawada Jun-ichi, Sui Guangchao, Affar El Bachir, Whetstine Johnathan R, Lan Fei, Ogawa Hidesato, Luke Margaret Po-Shan, Nakatani Yoshihiro, Shi Yang
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature. 2003 Apr 17;422(6933):735-8. doi: 10.1038/nature01550.
The transcriptional co-repressor CtBP (C-terminal binding protein) is implicated in tumorigenesis because it is targeted by the adenovirus E1A protein during oncogenic transformation. Genetic studies have also identified a crucial function for CtBP in animal development. CtBP is recruited to DNA by transcription factors that contain a PXDLS motif, but the detailed molecular events after the recruitment of CtBP to DNA and the mechanism of CtBP function in tumorigenesis are largely unknown. Here we report the identification of a CtBP complex that contains the essential components for both gene targeting and coordinated histone modifications, allowing for the effective repression of genes targeted by CtBP. Inhibiting the expression of CtBP and its associated histone-modifying activities by RNA-mediated interference resulted in alterations of histone modifications at the promoter of the tumour invasion suppressor gene E-cadherin and increased promoter activity in a reporter assay. These findings identify a molecular mechanism by which CtBP mediates transcriptional repression and provide insight into CtBP participation in oncogenesis.
转录共抑制因子CtBP（C末端结合蛋白）与肿瘤发生有关，因为在致癌转化过程中它是腺病毒E1A蛋白的作用靶点。遗传学研究也已确定CtBP在动物发育中具有关键功能。CtBP通过含有PXDLS基序的转录因子被招募到DNA上，但CtBP被招募到DNA后详细的分子事件以及CtBP在肿瘤发生中的功能机制很大程度上尚不清楚。在此，我们报告鉴定出一种CtBP复合物，其包含基因靶向和协同组蛋白修饰的必需成分，从而能够有效抑制CtBP靶向的基因。通过RNA介导的干扰抑制CtBP及其相关组蛋白修饰活性的表达，导致肿瘤侵袭抑制基因E-钙黏蛋白启动子处组蛋白修饰的改变，并在报告基因检测中增加了启动子活性。这些发现确定了CtBP介导转录抑制的分子机制，并为CtBP参与肿瘤发生提供了深入了解。
