Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway

Pitx2 is a bicoid-related homeodomain factor that is required for effective cell type-specific proliferation directly activating a specific growth-regulating gene cyclin D2. Here, we report that Pitx2, in response to the Wnt/beta-catenin pathway and growth signals, also can regulate c-Myc and cyclin D1. Investigation of molecular mechanisms required for Pitx2-dependent proliferation, in these cases, further supports a nuclear role for beta-catenin in preventing the histone deacetylase 1-dependent inhibitory functions of several DNA-binding transcriptional repressors, potentially including E2F4/p130 pocket protein inhibitory complex, as well as lymphoid enhancer factor 1 and Pitx2, by dismissal of histone deacetylase 1 and loss of its enzymatic activity. Thus, beta-catenin plays a signal-integrating role in Wnt- and growth factor-dependent proliferation events in mammalian development by both derepressing several classes of repressors and by activating Pitx2, regulating the activity of several growth control genes.