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Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21

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...

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Published in:The Journal of biological chemistry 2014-01, Vol.289 (1), p.581-593
Main Authors: Basu, Nirmalya, Saha, Sayanti, Khan, Imran, Ramachandra, Subbaraya G., Visweswariah, Sandhya S.
Format: Article
Language:English
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Summary: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. Receptor guanylyl cyclase C regulates ion secretion and cytostasis in intestinal epithelial cells. Ligand-mediated activation of guanylyl cyclase C and subsequent elevation of cGMP increase levels of p21 via PKGII and p38 MAPK. Guanylyl cyclase C can induce intestinal epithelial cell cytostasis and senescence via p21. Intestinal neoplasia is controlled by cGMP and p21.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.511311