Gastrin stabilises β-catenin protein in mouse colorectal cancer cells

Abstract

As gastrin may play a role in the pathophysiology of gastrointestinal (GI) malignancies, the elucidation of the mechanisms governing gastrin-induced proliferation has recently gained considerable interest. Several studies have reported that a large percentage of colorectal tumours overexpress or stabilise the b-catenin oncoprotein. We thus sought to determine whether gastrin might regulate b-catenin expression in colorectal tumour cells. Amidated gastrin-17 (G-17), one of the major circulating forms of gastrin, not only enhanced b-catenin protein expression, but also one of its target genes, cyclin D1. Furthermore, activation of b-catenin-dependent transcription by gastrin was confirmed by an increase in LEF-1 reporter activity, as well as enhanced cyclin D1 promoter activity. Finally, G-17 prolonged the t 1/2 of b-catenin protein, demonstrating that gastrin appears to exert its mitogenic effects on colorectal tumour cells, at least in part, by stabilising b-catenin.

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

“…2A). p␤-Cat 33,37,41 , on the other hand, increased significantly after NEMO treatment, suggesting that NEMO may be facilitating activation of kinases such as GSK-3␤, thereby promoting phosphorylation of ␤-catenin at serine 33 and 37 residues in P colonic crypts. Bar graphs in Fig.…”

“…As a continuation of the studies, the possible contribution of the Wnt/␤-catenin pathway was examined in the observed biological effects of progastrin. Casein kinase I⑀ (CKI⑀) and GSK-3␤ phosphorylate ␤-catenin at Ser 45 (p␤-cat 45 ) and Thr 41 /Ser 37,33 (p␤-cat 33,37,41 ) residues, thereby facilitating its ubiquitination and proteasomal degradation (20). Total crypt extracts, probed by Western blotting, demonstrated significant increases in levels of p␤-cat 45 in proximal colons of Fabp-PG (Tg) versus WT mice (Fig.…”

“…To determine whether decreases in cellular levels of the phosphorylated ␤-catenin species in response to the NEMO peptide affected their nuclear import, we next probed crypt nuclear extracts with antibodies for p␤-cat 45 , p␤-cat 552 , and p␤-cat 33,37,41 . Relative levels of nuclear p␤-cat 45 and p␤-cat 552 were significantly elevated in nuclear extracts of control peptide-treated mice (Fig.…”

Phospholipase D Meets Wnt Signaling: A New Target for Cancer Therapy

“…Several Wnt target genes (Gastrin, FGF, c-Met, Tiam1, and Pygopus) are known to activate the Wnt/b-catenin signaling pathway (25)(26)(27)(28)(29). Gastrin, which plays a central role in the pathophysiology of gastrointestinal malignancies, enhances Figure 1.…”

“…b-catenin/TCF-dependent transcription activity through stabilization of b-catenin in colorectal cancer cells (25). FGF stabilizes b-catenin by downregulating GSK3b activity (26).…”