The Calcium-Sensing Receptor - A Driver of Colon Cell Differentiation

Author(s): J. F. Whitfield .

Journal Name: Current Pharmaceutical Biotechnology

Volume 10 , Issue 3 , 2009

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Abstract:

Dietary Ca2+ reduces colon cell proliferation and carcinogenesis, but it becomes ineffective or even tumorpromoting during carcinogenesis. It appears that Ca2+ and the colon cell CaSR together brake the massive cell production in normal colon crypts. The rapid proliferation of the transit-amplifying (TA) progeny of the colon stem cells at the bases of the crypts is driven by the “Wnt” signaling mechanism that stimulates proliferogenic genes and prevents apoptogenesis. It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough external Ca2+ to stimulate the expression of CaSRs, the signals from which stimulate the expression of E-cadherin. At this point the APC (adenomatous polyposis coli) protein appears and some of it enters the nucleus. There it removes the apoptogenesis shield and stops the β-catenin • Tcf-4 complex from driving further TA cell proliferation by releasing β-catenin from the nucleus, and delivering it to cytoplasmic APC • axin • GSK-3β complexes for ultimate proteasomal destruction. Cytoplasmic β-catenin is prevented from returning to the nucleus by destruction in APC • axin • GSK-3β complexes or locked by the emerging E-cadherin into adherens junctions which link the cell to proliferatively shut-down functioning cells with APC-dependent cytoskeletons moving up and out of the crypt. A common first step in colon carcinogenesis is the loss of functional APC which results in the retention of proliferogenic nuclear β- catenin • Tcf-4. This drives the eventual appearance of mutation accumulating, apoptosis-resistant clones the proliferation of which cannot be inhibited by external Ca2+ because of CaSR-disabling gene mutations.

Keywords: APC, Apoptosis, β-catenin, Ca2+, CaSR

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Article Details

VOLUME: 10
ISSUE: 3
Year: 2009
Page: [311 - 316]
Pages: 6
DOI: 10.2174/138920109787847510
Price: $58

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