Intestinal cell proliferation and senescence are regulated by receptor guanylyl cyclase C and p21
| Autor: | Imran Khan, S. G. Ramachandra, Sayanti Saha, Sandhya S. Visweswariah, Nirmalya Basu |
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| Rok vydání: | 2013 |
| Předmět: |
inorganic chemicals
Cyclin-Dependent Kinase Inhibitor p21 Cell cycle checkpoint genetic structures Receptors Peptide Colon Guanylin Receptors Enterotoxin Biology Biochemistry Mice Cell Line Tumor Cyclic GMP-Dependent Protein Kinases Animals Humans heterocyclic compounds Molecular Biology Cellular Senescence Cell Proliferation Mice Knockout Cell growth Cell Biology Guanylate cyclase 2C Cell cycle Intestinal epithelium Cell biology Up-Regulation Receptors Guanylate Cyclase-Coupled cardiovascular system sense organs Tumor Suppressor Protein p53 Cell aging Intracellular Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 289(1) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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