la,25-Dihydroxyvitamin D3 [la,25(OH)2D31, a hormonally active form of vitamin D3, has been shown to modulate cell differentiation and tumor promotion. This report demonstrates that mRNA of the metallothionein (MT) gene was induced by la,25(OH)2D3 in cultured epidermal keratinocytes and also in liver, kidney, and skin tissues when la-hydroxyvitamin D3, a synthetic precursor of lai,25(OH)2D3, was applied in vivo. Exposure of FRSK cells, a cell line derived from fetal -at skin keratinocytes, to la,25(OH)2D3 at 5 ng/ml (12 nM) increased MT mRNA to almost the same extent as that induced by 10 jcM dexamethasone or 1 ,LM CdCl2. This increase in the level of MT mRNA was evident within 2 hr and was maximal 12-24 hr after the addition of la,25(OH)2D3. (9). Furthermore, we found that la,25(OH)2D3 inhibited tumor promotion by phorbol 12-O-tetradecanoate 13-acetate (TPA) and mezerein in mouse skin (10). It also inhibited induction of ornithine decarboxylase by tumor promoters in the skin, stomach, colon, and liver (11, 12). In cell culture systems, however, this hormone was found to enhance chemical transformation of BALB 3T3 (13,14) and Syrian hamster cells (15) and also to induce anchorage-independent growth of JB6 (16), BALB 3T3, and NIH 3T3 (17) cells. The apparent discrepancy between its effects on tumor promotion in vitro and in vivo requires further study, especially at the molecular level.Identification of genes that are regulated by la,25(0H)2D3 and the mechanisms of its regulatory effect are of particular importance. Calcium binding protein was shown to be induced in rat intestine by la,25(0H)2D3 (18). DeLuca and his colleagues (19) reported that four distinct mRNAs were significantly increased in rat intestine when la,25(0H)2D3 was applied to vitamin D-deficient animals: these were vitamin D-dependent calcium-binding protein, mitochondrial ATP synthetase, and cytochrome oxidase subunits I and III. We found (17) that la,25(OH)2D3 induced expression of the c-Ki-ras gene in BALB 3T3 and NIH 3T3 cells.In this study, we found that mRNA of the MT gene was induced by la,25(0H)2D3 in cultured epidermal keratinocytes and also in liver, kidney, and skin tissues when la-hydroxyvitamin D3 [la(OH)D3], a synthetic precursor of la,25(OH)2D3, was applied in vivo. This induction of MTs may be relevant to some biological actions of la,25(OH)2D3. la(OH)D3, la-hydroxyvitamin D3. §To whom all correspondence should be addressed.
MATERIALS AND METHODS
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