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
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Nat Chem Biol. 2009 Feb;5(2):100-7. doi: 10.1038/nchembio.137. Epub 2009 Jan 4.
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 new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-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/beta-catenin pathway response in vivo, and we 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.
分泌型Wnt信号蛋白在组织稳态和肿瘤发生过程中的广泛影响激发了人们寻找靶向Wnt介导的细胞反应的小分子的努力。通过筛选一个多样化的合成化学文库，我们发现了两类新的小分子，它们能够破坏Wnt信号通路反应；其中一类抑制豪猪蛋白（Porcupine）的活性，豪猪蛋白是一种膜结合酰基转移酶，对Wnt蛋白的产生至关重要，另一类则消除了Axin蛋白的降解，Axin蛋白是Wnt/β-连环蛋白信号通路活性的抑制剂。利用这些小分子，我们建立了一种化学遗传学方法来研究成年组织中的Wnt信号通路反应和干细胞功能。我们在体内实现了Wnt/β-连环蛋白信号通路反应的瞬时、可逆抑制，并且建立了一种基于机制的方法来靶向癌细胞生长。此处显示的可化学操控的信号转导机制还对不依赖Wnt的信号转导通路有作用，因此可广泛用于化学遗传学和治疗目的。
