Evidence for a function of CtBP in epithelial gene regulation and anoikis
Evidence for a function of CtBP in epithelial gene regulation and anoikis
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DOI：
10.1038/sj.onc.1203721
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发表时间：
2000-08-03
期刊：
影响因子：
8
通讯作者：
Frisch, SM
中科院分区：
文献类型：
--
作者：
Grooteclaes, ML;Frisch, SM
以前，我们报道了腺病毒E1 a蛋白在人类细胞中表现为肿瘤抑制因子。它显然通过转录诱导一系列上皮细胞粘附基因而发挥作用，同时抑制其他细胞类型特异性基因，从而产生上皮表型。同时，细胞变得对失巢凋亡（从细胞外基质脱离的上皮细胞的凋亡）敏感，可能导致肿瘤抑制。E1 a蛋白与核乙酰化酶p300、CBP和P/CAF相互作用，也与辅阻遏蛋白CtBP相互作用。在这项研究中，我们已经确定了E1 a对人类肿瘤细胞的表型效应中这些相互作用的作用。结果表明，E1 a与CtBP的相互作用激活至少三个上皮细胞粘附基因启动子。E-cadherin阻遏物似乎是CtBP相互作用蛋白delta EF 1/ZEB，其结合E-cadherin启动子的ras阻遏的E-box。E1 a-CtBP相互作用也促进了失巢凋亡增敏。E1 a与核乙酰化酶的相互作用赋予上皮形态，但不激活上皮基因。这些后者的相互作用并不使肿瘤细胞对失巢凋亡敏感，但仍然赋予肿瘤抑制作用。这些结果暗示CtBP作为上皮表型和失巢凋亡的拮抗剂，它们还表明核乙酰化酶在维持转化表型中的新的但未确定的作用。
Previously, we reported that adenovirus E1a protein behaves as a tumor suppressor in human cells. It apparently functions by transcriptionally inducing an array of epithelial cell adhesion genes, while repressing other cell-type specific genes, thus producing an epithelial phenotype. Concomitantly, the cells become sensitive to anoikis (apoptosis of epithelial cells detached from extracellular matrix), potentially causing tumor suppression. E1a protein interacts with the nuclear acetylases p300, CBP and P/CAF, and also with the co-repressor protein CtBP. In this study, we have determined the role of these interactions in E1a's phenotypic effects on human tumor cells. The results indicate that E1a's interaction with CtBP activates at least three epithelial cell adhesion gene promoters. The E-cadherin repressor appeared to be the CtBP-interacting protein delta EF1/ZEB, which bound the ras-repressible E-boxes of the E-cadherin promoter. The E1a-CtBP interaction also contributed to anoikis-sensitization. E1a's interactions with the nuclear acetylases conferred epithelial morphologies but did not activate epithelial genes. These latter interactions did not sensitize tumor cells to anoikis but nevertheless conferred tumor suppression. These results implicate CtBP as an antagonist of the epithelial phenotype and anoikis, They also indicate a new but undefined role for nuclear acetylases in maintaining the transformed phenotype.