All-trans retinoic acid blocks the antiproliferative prodifferentiating actions of 1,25-Dihydroxyvitamin D3 in normal human keratinocytes
✍ Scribed by David F. C. Gibson; Daniel D. Bikle; Jonathan Harris
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 261 KB
- Volume
- 174
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
1,25-Dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and all-trans retinoic acid (RA), the active metabolites of vitamins D and A respectively, regulate the proliferation and differentiation of keratinocytes. Both the vitamin D receptor (VDR) and the retinoic acid receptor family (RAR) bind to DNA response elements as heterodimers with the retinoic X receptor (RXR), suggesting that there are pathways of action that are shared by both compounds. Therefore, we examined the interactions of 1,25(OH) 2 D 3 and RA upon the proliferation and differentiation of normal human keratinocytes (NHK) and of a squamous cell carcinoma cell line, SCC4. Although both 1,25(OH) 2 D 3 and RA were each able to inhibit NHK proliferation in a dosedependent manner, when they were administered in combination, proliferation was stimulated, suggesting mutual antagonism. In contrast, SCC4 cells proved insensitive in terms of proliferation to 1,25(OH) 2 D 3 and to all but the highest concentration (10 06 M) of RA. 1,25(OH) 2 D 3 exerted a biphasic effect on transglutaminase (TGase) and involucrin (INV) mRNA levels, with maximal stimulation at 10 09 M. RA inhibited TGase and INV mRNA levels and antagonized the stimulation by 1,25(OH) 2 D 3 . A similar pattern was observed for TGase protein, but, RA, which, by itself, reduced INV, markedly enhanced the ability of 1,25(OH) 2 D 3 to raise INV levels, possibly by inhibiting 1,25(OH) 2 D 3 -stimulated TGase activity and cross-linking of soluble INV into the insoluble cornified envelope (CE). Thus, in NHK cells, RA antagonizes the antiproliferative prodifferentiating actions of 1,25(OH) 2 D 3 , but assessment of a single marker, such as INV protein, may be misleading.