Calcium- and vitamin D-regulated keratinocyte differentiation

Calcium and 1,25 dihydroxyvitamin D (1,75(OH)(2)D) regulate the differentia tion of keratinocytes. We have examined the mechanisms by which such regula tion takes place, focusing primarily on the events leading to cornified env elope (CE) formation, in particular the mechanisms by which calcium and 1,2 5(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 in tracellular free calcium (Ca-i) as a necessary step toward stimulating diff erentiation. Cells lacking the calcium sensing receptor (CaR) or phospholip ase C-gamma1 (PLC-gamma1) fail to respond to Ca, or 1,25(OH)(2)D with respe ct to differentiation. Residing in the promoter of involucrin is a region r esponsive 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 respo nsiveness to Ca, 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-ind uced differentiation. Thus, the regulation of keratinocyte differentiation by calcium and 1,25(OH)(2)D involves a number of signaling pathways includi ng PLC and PKC activation, leading to the induction of proteins required fo r the differentiation process. (C) 2001 Elsevier Science Ireland Ltd. All r ights reserved.