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

共 49 条

[21] Blockade of Protein Geranylgeranylation Inhibits Cdk2-Dependent p27Kip1 Phosphorylation on Thr187 and Accumulates p27Kip1 in the Nucleus: Implications for Breast Cancer Therapy [J].

Kazi, Aslamuzzaman ;

Carie, Adam ;

Blaskovich, Michelle A. ;

Bucher, Cynthia ;

Thai, Van ;

Moulder, Stacy ;

Peng, Hairuo ;

Carrico, Dora ;

Pusateri, Erin ;

Pledger, Warren J. ;

Berndt, Norbert ;

Hamilton, Andrew ;

Sebti, Said M. .

MOLECULAR AND CELLULAR BIOLOGY, 2009, 29 (08) :2254-2263

[22] Repressor activity of headless/Tcf3 is essential for vertebrate head formation [J].

Kim, CH ;

Oda, T ;

Itoh, M ;

Jiang, D ;

Artinger, KB ;

Chandrasekharappa, SC ;

Driever, W ;

Chitnis, AB .

NATURE, 2000, 407 (6806) :913-916

[23]

KINSELLA BT, 1991, J BIOL CHEM, V266, P9786

[24] IDENTIFICATION OF FAP LOCUS GENES FROM CHROMOSOME-5Q21 [J].

KINZLER, KW ;

NILBERT, MC ;

SU, LK ;

VOGELSTEIN, B ;

BRYAN, TM ;

LEVY, DB ;

SMITH, KJ ;

PREISINGER, AC ;

HEDGE, P ;

MCKECHNIE, D ;

FINNIEAR, R ;

MARKHAM, A ;

GROFFEN, J ;

BOGUSKI, MS ;

ALTSCHUL, SF ;

HORII, A ;

ANDO, H ;

MIYOSHI, Y ;

MIKI, Y ;

NISHISHO, I ;

NAKAMURA, Y .

SCIENCE, 1991, 253 (5020) :661-665

[25] Wnt signalling and its impact on development and cancer [J].

Klaus, Alexandra ;

Birchmeier, Walter .

NATURE REVIEWS CANCER, 2008, 8 (05) :387-398

[26] Wnt11/β-catenin signaling in both oocytes and early embryos acts through LRP6-mediated regulation of axin [J].

Kofron, Matt ;

Birsoy, Bilge ;

Houston, Douglas ;

Tao, Qinghua ;

Wylie, Christopher ;

Heasman, Janet .

DEVELOPMENT, 2007, 134 (03) :503-513

[27] Endoplasmic reticulum potassium-hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes [J].

Kuum, Malle ;

Veksler, Vladimir ;

Liiv, Joanna ;

Ventura-Clapier, Renee ;

Kaasik, Allen .

JOURNAL OF CELL SCIENCE, 2012, 125 (03) :625-633

[28] ECTOPIC EXPRESSION OF THE PROTO-ONCOGENE INT-1 IN XENOPUS EMBRYOS LEADS TO DUPLICATION OF THE EMBRYONIC AXIS [J].

MCMAHON, AP ;

MOON, RT .

CELL, 1989, 58 (06) :1075-1084

[29] GSK-3-selective inhibitors derived from Tyrian purple indirubins [J].

Meijer, L ;

Skaltsounis, AL ;

Magiatis, P ;

Polychronopoulos, P ;

Knockaert, M ;

Leost, M ;

Ryan, XZP ;

Vonica, CA ;

Brivanlou, A ;

Dajani, R ;

Crovace, C ;

Tarricone, C ;

Musacchio, A ;

Roe, SM ;

Pearl, L ;

Greengard, P .

CHEMISTRY & BIOLOGY, 2003, 10 (12) :1255-1266

[30] Genetics of programmed cell death in C-elegans:: past, present and future [J].

Metzstein, MM ;

Stanfield, GM ;

Horvitz, HR .

TRENDS IN GENETICS, 1998, 14 (10) :410-416

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