Intestinal cell proliferation and senescence are regulated by receptor guanylyl cyclase C and p21

J Biol Chem. 2014 Jan 3;289(1):581-93. doi: 10.1074/jbc.M113.511311. Epub 2013 Nov 11.


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.

Keywords: Cyclic GMP (cGMP); GCC Knock-out mice; Intestinal Epithelium; Microarray; Protein Kinase G (PKG); Receptor Guanylyl Cyclase C; Senescence; Sp1; T84 Cell; p21.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cellular Senescence*
  • Colon / metabolism*
  • Colon / pathology
  • Cyclic GMP-Dependent Protein Kinases / genetics
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled / genetics
  • Receptors, Guanylate Cyclase-Coupled / metabolism*
  • Receptors, Peptide / genetics
  • Receptors, Peptide / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation*


  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Receptors, Peptide
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Cyclic GMP-Dependent Protein Kinases
  • GUCY2C protein, human
  • Gucy2c protein, mouse
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled