A Zebrafish Chemical Suppressor Screening Identifies Small Molecule Inhibitors of the Wnt/β-catenin Pathway

被引：33
|
作者：
Nishiya, Naoyuki [1 ]
Oku, Yusuke [1 ]
Kumagai, Yusuke [1 ]
Sato, Yuki [1 ]
Yamaguchi, Emi [1 ]
Sasaki, Akari [1 ]
Shoji, Momoko [1 ]
Ohnishi, Yukimi [1 ]
Okamoto, Hitoshi [2 ]
Uehara, Yoshimasa [1 ]
机构：
[1] Iwate Med Univ, Sch Pharm, Dept Microbial Chem Biol & Drug Discovery, Yahaba, Iwate 0283694, Japan
[2] RIKEN Brain Sci Inst, Lab Dev Gene Regulat, Wako, Saitama 3510198, Japan
来源：
CHEMISTRY & BIOLOGY | 2014年 / 21卷 / 04期
关键词：
GERANYLGERANYLTRANSFERASE-I INHIBITOR; GLYCOGEN-SYNTHASE KINASE-3; BETA-CATENIN; PROTEIN PRENYLATION; CANCER-THERAPY; WNT; AXIN; PHOSPHORYLATION; ACTIVATION; SIGNAL;
D O I：
10.1016/j.chembiol.2014.02.015
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：
Genetic screening for suppressor mutants has been successfully used to identify important signaling regulators. Using an analogy to genetic suppressor screening, we developed a chemical suppressor screening method to identify inhibitors of the Wnt/beta-catenin signaling pathway. We used zebrafish embryos in which chemically induced beta-catenin accumulation led to an "eyeless" phenotype and conducted a pilot screening for compounds that restored eye development. This approach allowed us to identify geranylgeranyltransferase inhibitor 286 (GGTI-286), a geranylgeranyltransferase (GGTase) inhibitor. Our follow-up studies showed that GGTI-286 reduces nuclear localization of beta-catenin and transcription dependent on beta-catenin/T cell factor in mammalian cells. In addition to pharmacological inhibition, GGTase gene knockdown also attenuates the nuclear function of beta-catenin. Overall, we validate our chemical suppressor screening as a method for identifying Wnt/beta-catenin pathway inhibitors and implicate GGTase as a potential therapeutic target for Wnt-activated cancers.
引用
收藏
页码：530 / 540
页数：11
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