Mediator is a transducer of Wnt/beta-catenin signaling.
Mediator is a transducer of Wnt/beta-catenin signaling.
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发表时间：
2006
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通讯作者：
Seokjoong Kim;Xuan Xu;A. Hecht;T. Boyer
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作者：
Seokjoong Kim;Xuan Xu;A. Hecht;T. Boyer
经典Wnt/β-连环蛋白通路内的信号转导通过基因转录中的程序性或非程序性变化驱动发育和致癌。虽然与细胞质中β-连环蛋白的信号诱导激活相关的上游事件已被相当详细地破译，但关于β-连环蛋白刺激细胞核中靶基因转录的机制知之甚少。在这里，我们表明β-连环蛋白在物理和功能上靶向介导子中的MED 12亚基以激活转录。在体外和体内，β-连环蛋白反式激活结构域直接与分离的MED 12和完整的介体结合，并且介体以β-连环蛋白依赖性方式被募集到Wnt应答基因。通过显性负干扰或RNA干扰介导的MED 12抑制来破坏β-连环蛋白/MED 12相互作用，抑制了响应于Wnt信号传导的β-连环蛋白反式激活。因此，本研究将Mediator中的MED 12界面确定为Wnt/β-连环蛋白通路中的新组分和潜在治疗靶点。
Signal transduction within the canonical Wnt/beta-catenin pathway drives development and carcinogenesis through programmed or unprogrammed changes in gene transcription. Although the upstream events linked to signal-induced activation of beta-catenin in the cytoplasm have been deciphered in considerable detail, much less is known regarding the mechanism by which beta-catenin stimulates target gene transcription in the nucleus. Here, we show that beta-catenin physically and functionally targets the MED12 subunit in Mediator to activate transcription. The beta-catenin transactivation domain bound directly to isolated MED12 and intact Mediator both in vitro and in vivo, and Mediator was recruited to Wnt-responsive genes in a beta-catenin-dependent manner. Disruption of the beta-catenin/MED12 interaction through dominant-negative interference- or RNA interference-mediated MED12 suppression inhibited beta-catenin transactivation in response to Wnt signaling. This study thus identifies the MED12 interface within Mediator as a new component and a potential therapeutic target in the Wnt/beta-catenin pathway.