FIGURE 6.

Goblet cell hyperplasia in P colon of Fabp-PG mice. Ai, proximal and distal colons from WT and Fabp-PG (Tg/Tg) mice showing Alcian Blue staining to localize goblet cells. Aii, bar graph showing percent of total goblet cells/crypt from the two parts of the colon. B, effect of NEMO peptide treatment on goblet cell hyperplasia. Fabp-PG mice were divided into two groups and injected once a day for 4 days with either control (mutant) NEMO peptide (−) or NEMO peptide (+) as described in the legend to Fig. 2. Sections were stained with Alcian Blue. NEMO peptide treatment significantly blocked goblet cell hyperplasia in proximal but not distal colons (Bi). Bii, bar graph showing percent of total goblet cells/crypt from the colons of control (−) on NEMO peptide (+)-treated mice. C, proposed mechanism for a cross-talk between the IKKβ/NFκB and Wnt/β-catenin pathway. Progastrin interacts with its receptor ANXII, at the plasma membrane (33) and promotes intracellular signaling by up-regulating the IKKα,β/NFκB (18) and Wnt/β-catenin pathways (current studies) in colonic crypts. β-Catenin activation, however, was downstream to IKKα,β/NFκB, because NEMO peptide inhibited β-catenin activation via activating Tyr²¹⁶ phosphorylation of GSK-3β. NEMO peptide also blocked goblet cell hyperplasia implicating the IKKα,β/NFκB and/or Wnt/β-catenin pathways in its regulation. Therefore, the previously reported hyperproliferative and anti-apoptotic effects of progastrin on proximal colonic crypts in Fabp-PG mice (18) may have been mediated by the activation of both IKKαβ/NFκB and β-catenin pathways; the two pathways may be acting either in tandem or β-catenin may mediate all or some of the observed biological effects of progastrin.