Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
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DOI：
10.1038/nchembio.137
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发表时间：
2009-02
影响因子：
14.8
通讯作者：
Lum, Lawrence
中科院分区：
文献类型：
--
作者：
Chen, Baozhi;Dodge, Michael E.;Tang, Wei;Lu, Jianming;Ma, Zhiqiang;Fan, Chih-Wei;Wei, Shuguang;Hao, Wayne;Kilgore, Jessica;Williams, Noelle S.;Roth, Michael G.;Amatruda, James F.;Chen, Chuo;Lum, Lawrence
分泌的Wnt信号传导蛋白在组织稳态和肿瘤发生中的普遍影响已经激发了鉴定靶向Wnt介导的细胞应答的小分子的努力。通过筛选不同的合成化学文库，我们发现了两类破坏Wnt途径反应的新型小分子-其中一类抑制Porcupine（Porcn）的活性，Porcn是一种对Wnt蛋白产生至关重要的膜结合酰基转移酶，另一类消除了Axin蛋白的破坏，Wnt/β-连环蛋白途径活性的抑制剂。利用这些小分子，我们建立了一种化学遗传学方法，用于研究Wnt通路反应和成体组织中的干细胞功能。我们在体内实现了对Wnt/β-catenin通路反应的短暂、可逆的抑制，并建立了一种基于机制的靶向癌细胞生长的方法。这里显示的信号转导机制是化学上易处理的，另外有助于Wnt-独立的信号转导途径，因此可以广泛地用于化学遗传学和治疗目标。
The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two novel classes of small molecules that disrupt Wnt pathway responses - whereas one class inhibits the activity of Porcupine (Porcn), a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, suppressors of Wnt/β-catenin pathway activity. With these small molecules we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/β-catenin pathway response in vivo, and establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.
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