Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer

被引:1136
作者
Chen, Baozhi [1 ]
Dodge, Michael E. [1 ]
Tang, Wei [1 ]
Lu, Jianming [2 ]
Ma, Zhiqiang [2 ]
Fan, Chih-Wei [1 ]
Wei, Shuguang [2 ]
Hao, Wayne [2 ]
Kilgore, Jessica [2 ]
Williams, Noelle S. [2 ]
Roth, Michael G. [2 ]
Amatruda, James F. [3 ,4 ,5 ]
Chen, Chuo [2 ]
Lum, Lawrence [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA
[4] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
[5] Univ Texas SW Med Ctr Dallas, Dept Biol Mol, Dallas, TX 75390 USA
关键词
WNT/BETA-CATENIN; STEM-CELLS; BETA-CATENIN; PALMITOYLATION; ACYLTRANSFERASE; COMPARTMENTS; INTESTINE; PATHWAY; PROTEIN; LRP6;
D O I
10.1038/nchembio.137
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:100 / 107
页数:8
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