Tumor suppressor gene adenomatous polyposis coli downregulates intestinal transport

Abstract

Loss of function mutations of the tumor suppressor gene adenomatous polyposis coli (APC) underly the familial adenomatous polyposis. Mice carrying an inactivating mutation in the apc gene (apc (Min/+)) similarly develop intestinal polyposis. APC is effective at least in part by degrading β-catenin and lack of APC leads to markedly enhanced cellular β-catenin levels. β-Catenin has most recently been shown to upregulate the Na+/K+ ATPase. The present study, thus, explored the possibility that APC could influence intestinal transport. The abundance and localization of β-catenin were determined utilizing Western blotting and confocal microscopy, the activity of the electrogenic glucose carrier (SGLT1) was estimated from the glucose-induced current in jejunal segments utilizing Ussing chamber experiments and the Na+/H+ exchanger (NHE3) activity from Na+ -dependent re-alkalinization of cytosolic pH (ΔpH(i)) following an ammonium pulse employing BCECF fluorescence. As a result, β-catenin abundance in intestinal tissue was significantly higher in apc (Min/+) mice than in wild-type mice (apc (+/+)). The β-catenin protein was localized in the basolateral membrane. Both, the glucose-induced current and ΔpH(i) were significantly higher in apc (Min/+) mice than in apc (+/+) mice. In conclusion, intestinal electrogenic transport of glucose and intestinal Na+/H+ exchanger activity are both significantly enhanced in apc (Min/+) mice, pointing to a role of APC in the regulation of epithelial transport.

Chronic inflammation evoked by pathogenic stimulus during carcinogenesis

“…Silenced APC by promoter methylation was greater in HCC tissue than in noncancerous tissue and the level of APC protein expression was reduced in HCC [273]. The APC tumor suppressor gene also downregulates intestinal transport mediated by both electrogenic sodium-glucose transport protein 1 (SGLT1) and by the Na + /H + exchanger (NHE3) [274]. It increases the nuclear factor of activated T cells (NFAT) in a microtubule-dependent fashion.…”

Genetic and Diet-Induced Obesity Increased Intestinal Tumorigenesis in the Double Mutant Mouse Model Multiple Intestinal Neoplasia X Obese via Disturbed Glucose Regulation and Inflammation

“…This was not caused by higher feed intake since there were no significant differences in feed intake between Apc Min/+ and Apc +/+ mice ( Table 1 ), and the body weight was lower in Apc Min/+ mice than Apc +/+ mice for all three body weight scores ( Figure 1 , data not shown). A possible explanation is that APC is involved in regulation of epithelial glucose transport in the intestines, since Apc Min/+ mice had increased activity of the electrogenic glucose carrier (SGLT1) compared with Apc +/+ mice [ 60 ]. Apc is a component of the Wnt signaling pathway [ 5 , 6 ].…”

The Intrauterine and Nursing Period Is a Window of Susceptibility for Development of Obesity and Intestinal Tumorigenesis by a High Fat Diet inMin/+Mice as Adults

“…Also, the body weight was lower in Min/+ mice than in wild-type mice for body weight evaluated as AUC from day 3-4 to 11 weeks ( Figure 6 ) and as body weight at 11 weeks ( Figure 5 ). However, an alternative explanation for the difference in blood glucose levels may be that APC is involved in regulation of epithelial glucose transport in the intestines, since Min/+ mice had increased activity of the electrogenic glucose carrier (SGLT1) compared with wild-type mice [ 60 ]. APC is a component of the Wnt signaling pathway [ 19 , 20 ].…”