C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs
C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs
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DOI：
10.1073/pnas.0830998100
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发表时间：
2003-04-15
影响因子：
11.1
通讯作者：
Frisch, SM
中科院分区：
文献类型：
--
作者：
Grooteclaes, M;Deveraux, Q;Frisch, SM
癌细胞的发生通常涉及上皮细胞向间质细胞的转变和获得凋亡抵抗，但目前尚不清楚这些变化是协调控制的还是独立控制的。我们先前报道了腺病毒E1a在人肿瘤细胞中的作用，提出了E1a相互作用的辅阻遏物蛋白C末端结合蛋白(CtBP)可能选择性地抑制上皮细胞黏附和促凋亡基因的可能性。在这里，我们报告了CtBP基因敲除的细胞对凋亡高度敏感。相应地，对CtBP基因敲除的小鼠胚胎成纤维细胞与CtBP拯救的小鼠胚胎成纤维细胞的微阵列分析表明，许多上皮特异性和促凋亡基因确实受到CtBP的调控。CtBP的凋亡和抑制活性都不需要组氨酸-315，这表明所提出的脱氢酶活性对CtBP的功能不是必需的。本文提出的结果确立了CtBP的两个功能：核压上皮基因，从而允许上皮细胞向间充质细胞的转变，以及调节细胞凋亡反应的阈值。
The genesis of carcinoma cells often involves epithelial-to-mesenchymal transitions and the acquisition of apoptosis resistance, but it is unclear whether these alterations are controlled coordinately or independently. Our previously reported effects of adenovirus E1a in human tumor cells raised the possibility that the E1a-interacting corepressor protein C-terminal-binding protein (CtBP) might selectively repress epithelial cell adhesion and proapoptotic genes. Here, we report that CtBP-knockout cells were hypersensitive to apoptosis. Correspondingly, microarray analysis of CtBP-knockout vs. CtBP-rescued mouse embryo fibroblasts revealed that many epithelial-specific and proapoptotic genes were indeed regulated by CtBP. Neither the apoptosis nor the repression activities of CtBP required histidine-315, suggesting that the proposed dehydrogenase activity is not essential for CtBP function. The results presented herein establish two functional roles of CtBP: to core-press epithelial genes, thus permitting epithelial-to-mesenchymal transitions, and to modulate the cellular threshold for apoptotic responses.