Activation of NF-kappaB is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo.
Mice overexpressing progastrin (PG) in intestinal mucosa (fatty acid-binding protein (Fabp)-PG mice) are at an increased risk of proximal colon carcinogenesis in response to azoxymethane. Here, we report a significant increase in the length of proximal colonic crypts in Fabp-PG mice, associated with potent antiapoptotic effects of PG, which likely contributed to the previously reported increase in colon carcinogenesis in Fabp-PG mice. Phosphorylation of kinase of IkappaBalpha (IKKalpha/beta), inhibitor of kappaB (IkappaB)alpha and p65NF-kappaB was significantly elevated in proximal colonic crypts of Fabp-PG versus wild-type mice, which was associated with degradation of IkappaBalpha and nuclear translocation/activation of p65. Surprisingly, distal colonic crypt cells were not as responsive to elevated levels of PG in Fabp-PG mice. Annexin II, recently described as a high-affinity receptor for PG, strongly co-localized with PG intracellularly and on basolateral membranes of proximal crypt cells, providing evidence that annexin-II binds PG in situ in colonic crypt cells. Proliferative and antiapoptotic effects of PG on proximal crypts of Fabp-PG mice were attenuated to wild-type levels, on treatment with NEMO peptide (an inhibitor of nuclear factor-kappaB (NF-kappaB) activation), demonstrating for the first time a critical role of NF-kappaB in mediating hyperproliferative affects of PG on colonic crypts of Fabp-PG mice, in vivo. Thus, downregulation of NF-kappaB may significantly reduce the increased risk of colon carcinogenesis in response to PG.
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-1043, USA.
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Umar
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Sarkar
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Cowey
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Singh
D000818:Animals; D017306:Annexin A2 / Q000032:analysis; D017209:Apoptosis; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000209:etiology*; D004247:DNA / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000502:physiology; D005755:Gastrins / Q000032:analysis / Q000502:physiology*; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D011498:Protein Precursors / Q000032:analysis / Q000502:physiology*; D051996:Transcription Factor RelA / Q000032:analysis
D017306:Annexin A2; D050556:Fatty Acid-Binding Proteins; D005755:Gastrins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011498:Protein Precursors; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; C013706:big gastrin; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases