Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo
Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo
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DOI：
10.1073/pnas.0700240104
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发表时间：
2007-06-05
影响因子：
11.1
通讯作者：
Kitagawa, Motoo
中科院分区：
文献类型：
--
作者：
Oyama, Toshinao;Harigaya, Kenichi;Kitagawa, Motoo
Mam是Notch信号的组成部分之一，Notch信号是一个古老的系统，在后生动物的发育中起着关键作用。在果蝇和秀丽隐杆线虫的遗传分析表明，曼是一个重要的积极调节这一信号通路在这些物种。Mam蛋白结合并稳定细胞核中Notch和CBF-1、Su（H）、Lag-1（CSL）DNA结合蛋白的细胞内结构域的DNA结合复合物。哺乳动物有三种Mam蛋白，它们在功能上显示出显着的相似性，同时具有不寻常的结构多样性。最近也有迹象表明，Mam-1功能上与其他转录因子，包括p53肿瘤抑制因子相互作用。我们在本文中描述了小鼠中Mam-1缺乏会消除脾脏边缘区B细胞的发育，该细胞是严格依赖于Notch 2、一种CSL蛋白和Delta 1配体的亚群。Mam-1缺陷也会导致早期胸腺细胞发育部分受损，但不影响依赖Notch 1的造血过程。我们还证明了通过Notch的组成型活性形式的靶启动子的转录激活在培养的Mam-1-cleficient细胞中降低数倍。这些结果表明，Mam-1，因此需要在一定程度上的Notch依赖性阶段的淋巴细胞，从而支持的概念，Marn是一个重要组成部分的经典Notch途径在哺乳动物。
Mastermind (Mam) is one of the elements of Notch signaling, an ancient system that plays a pivotal role in metazoan development. Genetic analyses in Drosophila and Caenorhabditis elegans have shown Mann to be an essential positive regulator of this signaling pathway in these species. Mam proteins bind to and stabilize the DNA-binding complex of the intracellular domains of Notch and CBF-1, Su(H), Lag-1 (CSL) DNA-binding proteins in the nucleus. Mammals have three Mam proteins, which show remarkable similarities in their functions while having an unusual structural diversity. There have also been recent indications that Mam-1 functionally interacts with other transcription factors including p53 tumor suppressor. We herein describe that Mam-1 deficiency in mice abolishes the development of splenic marginal zone B cells, a subset strictly dependent on Notch2, a CSL protein and Delta1 ligand. Mam-1 deficiency also causes a partially impaired development of early thymocytes, while not affecting the generation of definitive hematopoiesis, processes that are dependent on Notch1. We also demonstrate the transcriptional activation of a target promoter by constitutively active forms of Notch to decrease severalfold in cultured Mam-l-cleficient cells. These results indicate that Mam-1 is thus required to some extent for Notch-dependent stages in lymphopoiesis, thus supporting the notion that Marn is an essential component of the canonical Notch pathway in mammals.