RRC ID |
33624
|
著者 |
Nishiya N, Oku Y, Kumagai Y, Sato Y, Yamaguchi E, Sasaki A, Shoji M, Ohnishi Y, Okamoto H, Uehara Y.
|
タイトル |
A zebrafish chemical suppressor screening identifies small molecule inhibitors of the Wnt/β-catenin pathway.
|
ジャーナル |
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.
|
巻・号 |
21(4)
|
ページ |
530-540
|
公開日 |
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
|
引用数 |
23
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
リソース情報 |
ゼブラフィッシュ |
RIKEN WT |