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

被引：35

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

页码：530 / 540

页数：11

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