|[Frontiers in Bioscience 1, a16-24, January 1, 1996]|
REGULATION OF INVOLUCRIN GENE EXPRESSION BY CALCIUM IN NORMAL HUMAN KERATINOCYTESDean C. Ng, Mei-Jhy Su, Richard Kim, and Daniel D. Bikle.
Endocrine Unit, VA Medical Center, University of California, 4150 Clement Street, 111N, San Francisco, CA 94121.
Received 12/7/95; Accepted 12/29/95; On-line 1/1/96
Calcium is essential for normal epidermal differentiation (1). In response to calcium, normal epidermal cells (keratinocytes) form cornified envelopes as a result of cross-linking of substrates such as involucrin by a specific membrane-bound enzyme, transglutaminase-1. Previous results from our laboratory have shown that the mRNA and protein levels of both involucrin and transglutaminase-1 were induced in a synergistic fashion by calcium and 1,25-Dihydroxyvitamin D3 in normal human keratinocytes (NHK) (2). The promoter of the involucrin gene has been previously identified (3), and a 3.7 Kbp 5' flanking region of the human involucrin gene cloned in front of a beta-galactosidase reporter has been demonstrated to be sufficient for the epidermal specific expression of the involucrin gene in transgenic mice (4).
The action of calcium on keratinocyte differentiation is exerted at multiple levels involving genomic and non-genomic events. At the genomic level, two examples can be cited. For genes that can be regulated by the cAMP response element (CRE), the activity of its binding protein (CREB) can be enhanced by calcium-dependent phosphorylation by calmodulin-dependent protein kinases (5-8). The AP-1 sites are well known to be regulated by phorbol esters by their activation of protein kinase C (PKC) (9,10). Recent reports suggest that calcium-induced c-fos and junB expression may in turn regulate the function of AP-1 sites (11,12).