4.4 Article

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

期刊

MOLECULAR BIOLOGY OF THE CELL
卷 28, 期 25, 页码 3699-3708

出版社

AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E17-01-0076

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资金

  1. Azm AMP
  2. Saade Association
  3. Agence Nationale de la Recherche Grant [ANR-11-LABX-0015]
  4. Grants-in-Aid for Scientific Research [16H05140] Funding Source: KAKEN

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The beta(4) isoform of the beta-subunits of voltage-gated calcium channel regulates cell proliferation and cell cycle progression. Herein we show that coexpression of the beta(4)-subunit with actors of the canonical Wnt/beta-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. beta(4)-subunit-mediated inhibition of Wnt signaling is observed in the presence of LiCl, an inhibitor of glycogen synthase kinase (GSK3) that promotes beta-catenin translocation to the nucleus. Expression of beta(4)-subunit mutants that lost the ability to translocate to the nucleus has no effect on Wnt signaling, suggesting that beta(4)-subunit inhibition of Wnt signaling occurs downstream from GSK3 and requires targeting of beta(4)-subunit to the nucleus. beta(4)-subunit coimmunoprecipitates with the TCF4 transcription factor and overexpression of TCF4 reverses the effect of beta(4)-subunit on the Wnt pathway. We thus propose that the interaction of nuclear beta(4)-subunit with TCF4 prevents beta-catenin binding to TCF4 and leads to the inhibition of the Wnt-responsive gene transcription. Thereby, our results show that beta(4)-subunit is a TCF4 repressor and therefore appears as an interesting candidate for the regulation of this pathway in neurons where beta(4)-subunit is specifically expressed.

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