Abstract
Guanylyl cyclase C (GC-C) is expressed in intestinal epithelial cells and serves as the receptor for bacterial heat-stable enterotoxin (ST) peptides and the guanylin family of gastrointestinal hormones. Activation of GC-C elevates intracellular cGMP, which modulates intestinal fluid-ion homeostasis and differentiation of enterocytes along the crypt-villus axis. GC-C activity can regulate colonic cell proliferation by inducing cell cycle arrest, and mice lacking GC-C display increased cell proliferation in colonic crypts. Activation of GC-C by administration of ST to wild type, but not Gucy2c(-/-), mice resulted in a reduction in carcinogen-induced aberrant crypt foci formation. In p53-deficient human colorectal carcinoma cells, ST led to a transcriptional up-regulation of p21, the cell cycle inhibitor, via activation of the cGMP-responsive kinase PKGII and p38 MAPK. Prolonged treatment of human colonic carcinoma cells with ST led to nuclear accumulation of p21, resulting in cellular senescence and reduced tumorigenic potential. Our results, therefore, identify downstream effectors for GC-C that contribute to regulating intestinal cell proliferation. Thus, genomic responses to a bacterial toxin can influence intestinal neoplasia and senescence.
Highlights
Receptor guanylyl cyclase C regulates ion secretion and cytostasis in intestinal epithelial cells
The absence of Guanylyl cyclase C (GC-C) in knock-out mice was correlated with a significant reduction (ϳ60%) in intracellular cyclic GMP (cGMP) levels in the colonic epithelia of Gucy2cϪ/Ϫ mice, whereas cAMP levels remained unchanged (Fig. 1C)
This study describes the process by which activation of GC-C initiates a transcriptional up-regulation of p21, resulting in cell cycle arrest and reduced tumorigenesis in colonic epithelia
Summary
Receptor guanylyl cyclase C regulates ion secretion and cytostasis in intestinal epithelial cells. Colonic epithelia of mice deficient in GC-C are prone to colonic tumors induced by carcinogens or inherited germ line mutations and demonstrate an accelerated cell cycle, disruption of genomic stability, and activation of protumorigenic signaling pathways [13, 14]. Uroguanylin and guanylin appear to play a key role in regulating the balance between proliferation and differentiation in the intestinal epithelia via cGMP and release of intracellular Ca2ϩ through cyclic nucleotide-gated channels [15]. Guanylin knock-out mice show increased crypt depth and a higher number of proliferating cells, reiterating the role of GC-C in regulating intestinal crypt biology [16]. We have delineated a signaling pathway emerging from GC-C whereby the up-regulation of p21 results in cellular cytostasis and induction of cellular senescence in intestinal epithelial cells
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