Calcium- and vitamin D-regulated keratinocyte differentiation.

Calcium and 1,25 dihydroxyvitamin D (1,25(OH)(2)D) regulate the differentiation of keratinocytes. We have examined the mechanisms by which such regulation takes place, focusing primarily on the events leading to cornified envelope (CE) formation, in particular the mechanisms by which calcium and 1,25(OH)(2)D regulate the induction of involucrin, a component of the CE, and transglutaminase, the enzyme cross-linking involucrin and other substrates to form the CE. Both extracellular calcium (Ca(o)) and 1,25(OH)(2)D raise intracellular free calcium (Ca(i)) as a necessary step toward stimulating differentiation. Cells lacking the calcium sensing receptor (CaR) or phospholipase C-gamma 1 (PLC-gamma 1) fail to respond to Ca(o) or 1,25(OH)(2)D with respect to differentiation. Residing in the promoter of involucrin is a region responsive to calcium and 1,25(OH)(2)D, the calcium response element (CaRE). The CaRE contains an AP-1 site, mutations of which result in loss of responsiveness to Ca(o) and 1,25(OH)(2)D, indicating a role for protein kinases C (PKC). PKC alpha is the major PKC isozyme involved at least for calcium-induced differentiation. Thus, the regulation of keratinocyte differentiation by calcium and 1,25(OH)(2)D involves a number of signaling pathways including PLC and PKC activation, leading to the induction of proteins required for the differentiation process.