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Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway.

ABSTRACT: The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/?-catenin signalling pathway in human cancer and normal cells as well as in mouse intestinal tissues. Furthermore, ?-catenin binds to TRF2 gene regulatory regions that are functional in a luciferase transactivating assay. Reduced ?-catenin expression in cancer cells triggers a marked increase in telomere dysfunction, which can be reversed by TRF2 overexpression. We conclude that the Wnt/?-catenin signalling pathway maintains a level of TRF2 critical for telomere protection. This is expected to have an important role during development, adult stem cell function and oncogenesis.

SUBMITTER: Diala I

PROVIDER: S-EPMC3615653 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

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Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway.

Diala Irmina I Wagner Nicole N Magdinier Frédérique F Shkreli Marina M Sirakov Maria M Bauwens Serge S Schluth-Bolard Caroline C Simonet Thomas T Renault Valérie M VM Ye Jing J Djerbi Abdelnnadir A Pineau Pascal P Choi Jinkuk J Artandi Steven S Dejean Anne A Plateroti Michelina M Gilson Eric E

EMBO reports 20130222 4

The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/β-catenin signalling pathway in human cancer and normal cells as well as in mouse intestinal tissues. Furthermore, β-catenin binds to TRF2 gene regulatory regions that are functional in a luciferase transactivating assay. Reduced β-catenin expression in cancer cells triggers a marked increase in telomere dysfunction, which can be reverse ...[more]

PMID: 23429341

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Project description:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

Dataset Information

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway.

Publications

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway.

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