Functional Cross-talk between β-Catenin and NFκB Signaling Pathways in Colonic Crypts of Mice in Response to Progastrin

We recently reported a critical role of NF kappa B in mediating hyperproliferative and anti-apoptotic effects of progastrin on proximal colonic crypts of transgenic mice overexpressing progastrin (Fabp-PG mice). We now report activation of beta-catenin in colonic crypts of mice in response to chronic (Fabp-PG mice) and acute (wild type FVB/N mice) progastrin stimulation. Significant increases were measured in relative levels of cellular and nuclear beta-catenin and p beta-cat(45) in proximal colonic crypts of Fabp-PG mice compared with that in wild type littermates. Distal colonic crypts were less responsive. Interestingly, beta-catenin activation was downstream of IKK alpha,beta/NF kappa B, because treatment of Fabp-PG mice with the NF kappa B essential modulator (NEMO) peptide (inhibitor of IKK alpha,beta/NF kappa B activation) significantly blocked increases in cellular/nuclear levels of total beta-catenin/p beta-cat(45)/and p beta-cat(552) in proximal colons. Cellular levels of p beta-cat(33,37,41), however, increased in proximal colons in response to NEMO, probably because of a significant increase in pGSK-3 beta(Tyr216), facilitating degradation of beta-catenin. NEMO peptide significantly blocked increases in cyclin D1 expression, thereby, abrogating hyperplasia of proximal crypts. Goblet cell hyperplasia in colonic crypts of Fabp-PG mice was abrogated by NEMO treatment, suggesting a cross-talk between the NF kappa B/beta-catenin and Notch pathways. Cellular proliferation and crypt lengths increased significantly in proximal but not distal crypts of FVB/N mice injected with 1 nM progastrin associated with a significant increase in cellular/nuclear levels of total beta-catenin and cyclin D1. Thus, intracellular signals, activated in response to acute and chronic stimulation with progastrin, were similar and specific to proximal colons. Our studies suggest a novel possibility that activation of beta-catenin, downstream to the IKK alpha,beta/NF kappa B pathway, may be integral to the hyperproliferative effects of progastrin on proximal colonic crypts.