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

The β(4) isoform of the β-subunits of voltage-gated calcium channel regulates cell proliferation and cell cycle progression. Herein we show that coexpression of the β(4)-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. β(4)-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 β(4)-subunit mutants that lost the ability to translocate to the nucleus has no effect on Wnt signaling, suggesting that β(4)-subunit inhibition of Wnt signaling occurs downstream from GSK3 and requires targeting of β(4)-subunit to the nucleus. β(4)-subunit coimmunoprecipitates with the TCF4 transcription factor and overexpression of TCF4 reverses the effect of β(4)-subunit on the Wnt pathway. We thus propose that the interaction of nuclear β(4)-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 β(4)-subunit is a TCF4 repressor and therefore appears as an interesting candidate for the regulation of this pathway in neurons where β(4)-subunit is specifically expressed.