Fig. 7.

Integration of three signaling pathways. Wnt signaling results in formation of Tcf-4/beta- - catenin complexes which activate expression from Wnt targeted genes; TCFbeta/Activin signaling is mediated by phosphorylated Smad2/3. In mock-treated HCT-116 cells, a limited amount of Dll1icd is bound to Tcf4 species, and likely to dephosphorylated Smad2/3; these transcriptional complexes might be repressive. In butyrate-treated HCT-116 cells, the steady-state levels of the Tcf4 species decrease, and some of the Tcf4 protein pool is recruited to Wnt signaling complexes with dephosphorylated beta-catenin. Butyrate-treated cells also exhibit increased levels of phosphorylated Smad2/3 (pSmad2/3) proteins. In a fraction of the cell population, the pSmad2/3 proteins are bound to Dll1icd, and the resulting complexes may activate a specific set of genes (e.g., CTGF, p21, etc). In the remainder of the cell population, the pSmad2/3 proteins bind to Nicd, and these complexes may modulate a different set of genes [80–82]. Our preliminary data suggest that cells with higher levels of Dll1icd respond to butyrate with greater hyper-activation of Wnt signaling, and higher levels of apoptosis. The cells with higher levels of Nicd may suppress the hyper-activation of Wnt/beta-catenin by butyrate, and are likely more resistant to apoptosis.