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

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

SUBMITTER: Rima M 

PROVIDER: S-EPMC5706996 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature