Signaling of monocytic differentiation by a non-hypercalcemic analog of vitamin D3, 1,25(OH)2-5,6 trans-16-ene-vitamin D3, involves nuclear vitamin D receptor (nVDR) and non-nVDR–mediated pathways
✍ Scribed by Yan Ji; Xuening Wang; Robert J. Donnelly; Milan R. Uskokovic; George P. Studzinski
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- English
- Weight
- 370 KB
- Volume
- 191
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Exposure of leukemia cells to the physiologically active form of vitamin D~3~, 1,25‐dihydroxyvitamin D~3~ (1,25D~3~) normalizes their phenotype to cells that resemble mature monocytes. One of the earliest detectable events in this process is an upregulation of the nuclear receptor for 1,25D~3~, the vitamin D receptor (nVDR). In contrast, the novel analog of 1,25D~3~, 1,25‐dihydroxy‐5,6 trans‐16‐ene‐vitamin D~3~ (5,6‐16D~3~), which has recently been reported to have low calcium‐mobilizing activity in vivo, rapidly induced the expression of CD14, CD11b, and monocyte‐specific esterase (MSE), classical markers of the mature monocyte, but upregulated nVDR expression less than 1,25D~3~. This upregulation was shown to be the result of altered degradation of the nVDR protein, while the levels of nVDR mRNA were constant. Knock‐out of nVDR transcriptional activity by a decoy VDRE double‐stranded deoxyoligonucleotide, markedly abrogated 1,25D~3~‐induced differentiation, but incompletely inhibited 5,6‐16D~3~‐induced differentiation. These findings suggest that the unique ability of 5,6‐16D~3~ to induce cell differentiation but not systemic hypercalcemia, may be due to the activation of pathways which initiate differentiation independently of nVDR. J. Cell. Physiol. 191: 198–207, 2002. © 2002 Wiley‐Liss, Inc.