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

Mohamad Rima, Marwa Daghsni, Anaïs Lopez, Ziad Fajloun, Lydie Lefrancois, Mireia Dunach, Yasuo Mori, Philippe Merle, Juan L. Brusés, Michel De Waard, Michel Ronjat

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)


© 2017 Rima, Daghsni, Lopez, et al. 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.
Original languageEnglish
Pages (from-to)3699-3708
JournalMolecular Biology of the Cell
Issue number25
Publication statusPublished - 1 Dec 2017


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