Oct25 Represses Transcription of Nodal/Activin Target Genes by Interaction with Signal Transducers during Xenopus Gastrulation
Oct25 Represses Transcription of Nodal/Activin Target Genes by Interaction with Signal Transducers during Xenopus Gastrulation
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DOI：
10.1074/jbc.m803532200
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发表时间：
2008-12-05
影响因子：
4.8
通讯作者：
Knoechel, Walter
中科院分区：
文献类型：
--
作者：
Cao, Ying;Siegel, Doreen;Knoechel, Walter
分化信号和维持胚胎细胞未分化状态的信号之间的平衡保证了胚层的正确形成。节点/激活素通路是胚胎细胞向中胚层和内胚层分化的主要信号链之一，而Oct4是维持未分化状态的主要参与者之一。本研究表明，Oct4在非洲爪蟾中的同系物Oct25通过抑制其靶基因Gsc和Mix2的转录来拮抗节点/激活素信号的活性。这种抑制作用是通过在Oct25与节点/激活素途径的信号转导WBSCR11、FAST1和Smad2之间形成抑制复合物，抑制Gsc和Mix2的启动子。我们分析了Oct结合位点在Gsc启动子内抑制作用的意义。尽管VP16-Oct25融合蛋白表现出刺激作用，EVE-Oct25对一个由8个Oct结合基序重复组成的人工报告蛋白表现出抑制作用，但这两种融合蛋白与野生型Oct25一样，都抑制了中胚层的形成以及Gsc和Mix2启动子的活性。这些结果表明，Oct25对Gsc和Mix2表达的调控作用是通过特定的蛋白/蛋白相互作用介导的。此外，我们证明了Oct25的抑制作用不需要组蛋白去乙酰化酶的活性。我们的研究结果提供了一个新的观点，即Oct25控制着节点/激活素通路，从而维持胚胎细胞的未分化状态，防止胚胎细胞过早分化。
The balance between differentiation signals and signals maintaining the undifferentiated state of embryonic cells ensures proper formation of germ layers. The nodal/activin pathway represents one of the major signaling chains responsible for the differentiation of embryonic cells into mesodermal and endodermal germ layers, while Oct4 is one of the major players in the maintenance of an undifferentiated state. Here we show that Oct25, an Oct4 homologue in Xenopus, antagonizes the activity of nodal/activin signaling by inhibiting the transcription of its target genes, Gsc and Mix2. The inhibitory effect is achieved by forming repression complexes on the promoters of Gsc and Mix2 between Oct25 and the signal transducers of the nodal/activin pathway, WBSCR11, FAST1, and Smad2. We have analyzed the significance of the Oct binding site for its inhibitory effect within the Gsc promoter. Albeit VP16-Oct25 fusion protein demonstrated a stimulating effect and EVE-Oct25 revealed a repression effect on an artificial reporter that is composed of eight repeats of Oct binding motifs, both fusions, like wild-type Oct25, inhibited mesendoderm formation and the activity of Gsc and Mix2 promoters. These results suggest that the regulatory effect of Oct25 on the expression of Gsc and Mix2 is mediated by specific protein/protein interactions. Furthermore, we demonstrate that histone deacetylase activities are not required for the inhibitory effect of Oct25. Our results provide a novel view in that Oct25 controls the nodal/activin pathway and thus maintains the undifferentiated state of embryonic cells in preventing them from premature differentiation.