Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4 - Centre de recherche en cancérologie de Lyon (UMR INSERM 1052 ; CNRS 5286 ; Centre Léon Bérard) Accéder directement au contenu
Article Dans Une Revue Molecular Biology of the Cell Année : 2017

Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4

Résumé

The β4 isoform of the β-subunits of voltage-gated calcium channel regulates cell proliferation and cell cycle progression. Herein we show that coexpression of the β4-subunit with actors of the canonical Wnt/β-catenin signaling pathway in a hepatoma cell line inhibits Wnt-responsive gene transcription and decreases cell division, in agreement with the role of the Wnt pathway in cell proliferation. β4-subunit-mediated inhibition of Wnt signaling is observed in the presence of LiCl, an inhibitor of glycogen synthase kinase (GSK3) that promotes β-catenin translocation to the nucleus. Expression of β4-subunit mutants that lost the ability to translocate to the nucleus has no effect on Wnt signaling, suggesting that β4-subunit inhibition of Wnt signaling occurs downstream from GSK3 and requires targeting of β4-subunit to the nucleus. β4-subunit coimmunoprecipitates with the TCF4 transcription factor and overexpression of TCF4 reverses the effect of β4-subunit on the Wnt pathway. We thus propose that the interaction of nuclear β4-subunit with TCF4 prevents β-catenin binding to TCF4 and leads to the inhibition of the Wnt-responsive gene transcription. Thereby, our results show that β4-subunit is a TCF4 repressor and therefore appears as an interesting candidate for the regulation of this pathway in neurons where β4-subunit is specifically expressed.

Dates et versions

hal-01832943 , version 1 (09-07-2018)

Identifiants

Citer

Mohamad Rima, Marwa Daghsni, Anaïs Lopez, Ziad Fajloun, Lydie Lefrancois, et al.. Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4. Molecular Biology of the Cell, 2017, Equipe IIb, 28 (25), pp.3699--3708. ⟨10.1091/mbc.E17-01-0076⟩. ⟨hal-01832943⟩
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