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

Basu, Nirmalya and Saha, Sayanti and Khan, Imran and Ramachandra, Subbaraya G and Visweswariah, Sandhya S (2014) Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21. In: JOURNAL OF BIOLOGICAL CHEMISTRY, 289 (1). pp. 581-593.

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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.

Item Type:	Journal Article
Publication:	JOURNAL OF BIOLOGICAL CHEMISTRY
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Additional Information:	Copyright for this article belongs to the AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, USA
Keywords:	Cyclic GMP (cGMP); Intestinal Epithelium; Microarray; Protein Kinase G (PKG); Senescence; Sp1; GCC Knock-out mice; T84 Cell; p21; Receptor Guanylyl Cyclase C
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	10 Feb 2014 10:19
Last Modified:	10 Feb 2014 10:19
URI:	http://eprints.iisc.ac.in/id/eprint/48333

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