Telomerase modulates Wnt signalling by association with target gene chromatin

被引：548

作者：

Park, Jae-Il ^{[1
]}

Venteicher, Andrew S. ^{[1
,2
]}

Hong, Ji Yeon ^{[4
]}

Choi, Jinkuk ^{[1
,3
]}

Jun, Sohee ^{[1
]}

Shkreli, Marina ^{[1
]}

Chang, Woody ^{[1
]}

Meng, Zhaojing ^{[5
]}

Cheung, Peggie ^{[1
]}

Ji, Hong ^{[4
]}

McLaughlin, Margaret ^{[6
,7
]}

Veenstra, Timothy D. ^{[5
]}

Nusse, Roel ^{[8
]}

McCrea, Pierre D. ^{[4
]}

Artandi, Steven E. ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Biophys Program, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Canc Biol Program, Stanford, CA 94305 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA

[5] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA

[6] MIT, Koch Inst Integrat Canc Biol, Cambridge, MA 02139 USA

[7] MIT, Dept Biol, Cambridge, MA 02139 USA

[8] Stanford Univ, Sch Med, Howard Hughes Med Inst, Dept Dev Biol, Stanford, CA 94305 USA

来源：

NATURE | 2009年 / 460卷 / 7251期

关键词：

BETA-CATENIN; REVERSE-TRANSCRIPTASE; ANTEROPOSTERIOR AXIS; TRANSIENT ACTIVATION; GROWTH; PROLIFERATION; EXPRESSION; OVEREXPRESSION; DYSFUNCTION; REGULATORS;

D O I：

10.1038/nature08137

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：

Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/beta-catenin signalling or overexpression of telomerase is sufficient to activate quiescent epidermal stem cells in vivo, although the mechanisms by which telomerase exerts these effects are not understood. Here we show that telomerase directly modulates Wnt/beta-catenin signalling by serving as a cofactor in a beta-catenin transcriptional complex. The telomerase protein component TERT (telomerase reverse transcriptase) interacts with BRG1 (also called SMARCA4), a SWI/SNF-related chromatin remodelling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior-posterior axis in Xenopus laevis embryos, and this defect in Wnt signalling manifests as homeotic transformations in the vertebrae of Tert(-/-) mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract shows that TERT physically occupies gene promoters of Wnt-dependent genes. These data reveal an unanticipated role for telomerase as a transcriptional modulator of the Wnt/beta-catenin signalling pathway.

引用

页码：66 / U77

页数：8

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