FIGURE 7.

Chronic ST treatment of mice elevates p21 levels in colonic epithelia and reduces cell proliferation. A, Western blot analysis of p21 and cyclin D1 expression in colonic crypts of Gucy2c^+/+ and Gucy2c^−/− mice treated with ST every 48 h for 10 days. Each lane represents individual mice (n = 3 for each treatment). The bottom panels show quantification of Western blots. Statistical significance was calculated using one-way analysis of variance with Tukey's multiple comparison test (**, p < 0.01; ***, p < 0.005). B, ligand-mediated (ST/uroguanylin/guanylin) activation of GC-C in the colonic cell leads to accumulation of cGMP, which in turn activates PKGII. This results in activation of the p38 MAPK pathway and phosphorylation of the Sp1 transcription factor, which enhances transcription of the p21 mRNA. Nuclear accumulation of p21 brings about senescence and quiescence, thereby reducing colorectal tumorigenesis. Known cytostatic pathways regulated by GC-C activation are shown in blue. CNG, cyclic nucleotide-gated channel; PTEN, phosphatase and tensin homolog.