RRC ID 33624
Author Nishiya N, Oku Y, Kumagai Y, Sato Y, Yamaguchi E, Sasaki A, Shoji M, Ohnishi Y, Okamoto H, Uehara Y.
Title A zebrafish chemical suppressor screening identifies small molecule inhibitors of the Wnt/β-catenin pathway.
Journal Chem. Biol.
Abstract 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/β-catenin signaling pathway. We used zebrafish embryos in which chemically induced β-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 β-catenin and transcription dependent on β-catenin/T cell factor in mammalian cells. In addition to pharmacological inhibition, GGTase gene knockdown also attenuates the nuclear function of β-catenin. Overall, we validate our chemical suppressor screening as a method for identifying Wnt/β-catenin pathway inhibitors and implicate GGTase as a potential therapeutic target for Wnt-activated cancers.
Volume 21(4)
Pages 530-540
Published 2014-4-24
DOI 10.1016/j.chembiol.2014.02.015
PII S1074-5521(14)00074-X
PMID 24684907
MeSH Alkyl and Aryl Transferases / antagonists & inhibitors* Alkyl and Aryl Transferases / metabolism Animals Dose-Response Relationship, Drug Eye / drug effects Eye / growth & development Leucine / analogs & derivatives* Leucine / chemistry Leucine / pharmacology Molecular Structure Small Molecule Libraries / chemistry Small Molecule Libraries / pharmacology* Structure-Activity Relationship Wnt Proteins / metabolism* Wnt Signaling Pathway / drug effects* Zebrafish / anatomy & histology Zebrafish / genetics Zebrafish / metabolism* beta Catenin / metabolism*
IF 5.915
Times Cited 14
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Zebrafish RIKEN WT