期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 2, 页码 1158-1167出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.274589
关键词
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资金
- National Institutes of Health [K22CA128883, K22CA128883-03S1, RO1-AG21353, RO1AR050023, RO1 AR055924, RO1DK054793, RO1DK56930, RO1DK55003, P30DK41301]
- Veteran Affairs Merit Review
Here, we examined the role of the extracellular Ca2+-sensing receptor (CaSR) in the control of colonic epithelial cell proliferation in vivo and changes in beta-catenin triggered by CaSR stimulation in human colonic epithelial cells in vitro. The in vivo studies, using a novel Casr intestinal-specific knock-out mouse, indicate that the genetic ablation of the Casr leads to hyperproliferation of colonic epithelial cells, expansion of the proliferative zone, changes in crypt structure, and enhanced beta-catenin nuclear localization. The in vitro results indicate that stimulation of the CaSR, by Ca2+ or by the calcimimetic R-568, produced a striking and time-dependent decrease in the phosphorylation of beta-catenin at Ser-552 and Ser-675, two amino acid residues that promote beta-catenin transcriptional activity. The reduced phosphorylation of beta-catenin coincided with a decline in its nuclear localization and a marked redistribution to the plasma membrane. Furthermore, CaSR stimulation promoted a down-regulation of beta-catenin-mediated transcriptional activation. These studies demonstrate that signaling pathways emanating from the CaSR control colonic epithelial cell proliferation in vivo and suggest that the mechanism involves regulation of beta-catenin phosphorylation.
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