Activator-to-repressor conversion of T-box transcription factors by the ripply family of Groucho/TLE-associated mediators
Activator-to-repressor conversion of T-box transcription factors by the ripply family of Groucho/TLE-associated mediators
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DOI：
10.1128/mcb.01754-07
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发表时间：
2008-05-01
影响因子：
5.3
通讯作者：
Takada, Shinji
中科院分区：
文献类型：
--
作者：
Kawamura, Akinori;Koshida, Sumito;Takada, Shinji
T-box转录因子家族由一个保守的DNA结合域T-box定义，通过激活和/或抑制下游基因来调节胚胎发生的各个方面。尽管T-box蛋白具有生物学意义，但它们如何调节转录仍有待阐明。在这里，我们展示了Groucho/ tle相关蛋白Ripply将T-box蛋白从激活因子转化为抑制因子。在培养细胞中，斑马鱼体细胞分割的重要组成部分Ripply1及其结构近亲Ripply2和-3抑制T-box蛋白Tbx24介导的转录激活，Tbx24在分割过程中与Ripply1共表达。Ripply1与Tbx24结合并将其转化为抑制因子。Ripply1还能拮抗另一种T-box蛋白No tail （Ntl）的转录激活，Ntl是Brachyury的斑马鱼同源物。此外，将高剂量的ripply1 mRNA注射到斑马鱼卵中会导致后躯干发育缺陷，类似于在ntl纯合突变体中观察到的表型。与Tbx24相关的Ripply1突变体在斑马鱼胚胎中也缺乏活性。这些结果表明，T-box蛋白的内在转录特性是由Ripply家族蛋白控制的，Ripply家族蛋白作为特异性接头，将全局共抑制因子Groucho/TLE招募到T-box蛋白上。
The T-box family of transcription factors, defined by a conserved DNA binding domain called the T-box, regulate various aspects of embryogenesis by activating and/or repressing downstream genes. In spite of the biological significance of the T-box proteins, how they regulate transcription remains to be elucidated. Here we show that the Groucho/TLE-associated protein Ripply converts T-box proteins from activators to repressors. In cultured cells, zebrafish Ripply1, an essential component in somite segmentation, and its structural relatives, Ripply2 and -3, suppress the transcriptional activation mediated by the T-box protein Tbx24, which is coexpressed with ripply1 during segmentation. Ripply1 associates with Tbx24 and converts it to a repressor. Ripply1 also antagonizes the transcriptional activation of another T-box protein, No tail (Ntl), the zebrafish ortholog of Brachyury. Furthermore, injection of a high dosage of ripply1 mRNA into zebrafish eggs causes defective development of the posterior trunk, similar to the phenotype observed in homozygous mutants of ntl. A mutant form of Ripply1 defective in association with Tbx24 also lacks activity in zebrafish embryos. These results indicate that the intrinsic transcriptional property of T-box proteins is controlled by Ripply family proteins, which act as specific adaptors that recruit the global corepressor Groucho/TLE to T-box proteins.