The calcium-sensing receptor--a driver of colon cell differentiation.
Dietary Ca(2+) reduces colon cell proliferation and carcinogenesis, but it becomes ineffective or even tumor-promoting during carcinogenesis. It appears that Ca(2+) 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 Ca(2+) 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 beta-cateninTcf-4 complex from driving further TA cell proliferation by releasing beta-catenin from the nucleus, and delivering it to cytoplasmic APCaxinGSK-3beta complexes for ultimate proteasomal destruction. Cytoplasmic beta-catenin is prevented from returning to the nucleus by destruction in APCaxinGSK-3beta 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 beta-cateninTcf-4. This drives the eventual appearance of mutation accumulating, apoptosis-resistant clones the proliferation of which cannot be inhibited by external Ca(2+) because of CaSR-disabling gene mutations.
Whitfield
J F
JF
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada. pthosteo@rogers.com
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology*; D003106:Colon / Q000166:cytology* / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D009369:Neoplasms / Q000473:pathology; D044169:Receptors, Calcium-Sensing / Q000502:physiology*
D044169:Receptors, Calcium-Sensing