共 30 条
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.
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页码:100 / 107
页数:8
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