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Transcription Factor 7-like 2 Mediates Canonical Wnt/?-Catenin Signaling and c-Myc Upregulation in Heart Failure.

ABSTRACT: How canonical Wnt/?-catenin signals in adult hearts, especially in different diseased states, remains unclear. The proto-oncogene, c-Myc, is a Wnt target and an early response gene during cardiac stress. It is not clear whether c-Myc is activated or how it is regulated during heart failure.We investigated canonical Wnt/?-catenin signaling and how it regulated c-Myc expression in failing hearts of human ischemic heart disease, idiopathic dilated cardiomyopathy, and murine desmin-related cardiomyopathy. Our data demonstrated that canonical Wnt/?-catenin signaling was activated through nuclear accumulation of ?-catenin in idiopathic dilated cardiomyopathy, ischemic heart disease, and murine desmin-related cardiomyopathy when compared with nonfailing controls and transcription factor 7-like 2 (TCF7L2) was the main ?-catenin partner of the T-cell factor (TCF) family in adult hearts. We further revealed that c-Myc mRNA and protein levels were significantly elevated in failing hearts by real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemical staining. Immunoprecipitation and confocal microscopy further showed that ?-catenin interacted and colocalized with TCF7L2. More importantly, chromatin immunoprecipitation confirmed that ?-catenin and TCF7L2 were recruited to the regulatory elements of c-Myc. This recruitment was associated with increased histone H3 acetylation and transcriptional upregulation of c-Myc. With lentiviral infection, TCF7L2 overexpression increased c-Myc expression and cardiomyocyte size, whereas shRNA-mediated knockdown of TCF7L2 suppressed c-Myc expression and cardiomyocyte growth in cultured neonatal rat cardiomyocytes.This study indicates that TCF7L2 mediates canonic Wnt/?-catenin signaling and c-Myc upregulation during abnormal cardiac remodeling in heart failure and suppression of Wnt/?-catenin to c-Myc axis can be explored for preventing and treating heart failure.

SUBMITTER: Hou N

PROVIDER: S-EPMC5060009 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure.

Hou Ning N Ye Bo B Li Xiang X Margulies Kenneth B KB Xu Haodong H Wang Xuejun X Li Faqian F

Circulation. Heart failure 20160614 6

<h4>Background</h4>How canonical Wnt/β-catenin signals in adult hearts, especially in different diseased states, remains unclear. The proto-oncogene, c-Myc, is a Wnt target and an early response gene during cardiac stress. It is not clear whether c-Myc is activated or how it is regulated during heart failure.<h4>Methods and results</h4>We investigated canonical Wnt/β-catenin signaling and how it regulated c-Myc expression in failing hearts of human ischemic heart disease, idiopathic dilated card ...[more]

PMID: 27301468

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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

Transcription Factor 7-like 2 Mediates Canonical Wnt/?-Catenin Signaling and c-Myc Upregulation in Heart Failure.

Publications

Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure.

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