WIKI4, a Novel Inhibitor of Tankyrase and Wnt/β-Catenin Signaling

被引：78

作者：

James, Richard G. ^{[1
,2
,5
]}

Davidson, Kathryn C. ^{[1
,2
,3
,5
]}

Bosch, Katherine A. ^{[1
,2
,3
,5
]}

Biechele, Travis L. ^{[1
,2
,3
,5
]}

Robin, Nicholas C. ^{[1
,2
,3
,5
]}

Taylor, Russell J. ^{[1
,2
,5
]}

Major, Michael B. ^{[6
]}

Camp, Nathan D. ^{[1
,2
,3
,5
]}

Fowler, Kerry ^{[7
]}

Martins, Timothy J. ^{[2
,4
,5
]}

Moon, Randall T. ^{[1
,2
,3
,5
]}

机构：

[1] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA

[2] Inst Stem Cell & Regenerat Med, Seattle, WA USA

[3] Howard Hughes Med Inst, Seattle, WA USA

[4] Quellos High Throughput Screening Core, Seattle, WA USA

[5] Univ Washington, Sch Med, Seattle, WA USA

[6] Univ North Carolina Chapel Hill, Dept Cell & Dev Biol, Chapel Hill, NC USA

[7] KWF Consulting, Seattle, WA USA

来源：

PLOS ONE | 2012年 / 7卷 / 12期

基金：

美国国家卫生研究院;

关键词：

EMBRYONIC STEM-CELLS; BETA-CATENIN; SULFATE PROTEOGLYCAN; MOUSE DEVELOPMENT; PATHWAY; ACTIVATION; DIFFERENTIATION; REGENERATION; REQUIREMENT; GROWTH;

D O I：

10.1371/journal.pone.0050457

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The Wnt/beta-catenin signaling pathway controls important cellular events during development and often contributes to disease when dysregulated. Using high throughput screening we have identified a new small molecule inhibitor of Wnt/beta-catenin signaling, WIKI4. WIKI4 inhibits expression of beta-catenin target genes and cellular responses to Wnt/beta-catenin signaling in cancer cell lines as well as in human embryonic stem cells. Furthermore, we demonstrate that WIKI4 mediates its effects on Wnt/beta-catenin signaling by inhibiting the enzymatic activity of TNKS2, a regulator of AXIN ubiquitylation and degradation. While TNKS has previously been shown to be the target of small molecule inhibitors of Wnt/beta-catenin signaling, WIKI4 is structurally distinct from previously identified TNKS inhibitors.

引用

页数：10

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