1,25-DIHYDROXYVITAMIN-D-3 DESTABILIZES C-MYC MESSENGER-RNA IN HL-60 LEUKEMIC-CELLS

The differentiation process is accompanied by alterations in the expression of a variety of genes. Monocytic maturation of hematopoietic cells (HL-60) induced by 1,25-dihydroxyvitamin D-3 (1,25(OH)2D3), results in a decrease in steady state c-myc mRNA levels. To elucidate the mechanism by which 1,25(OH)2D3 regulates c-myc mRNA expression, transcriptional and post-transcriptional modes of regulation were investigated. No transcriptional regulation was identified, however, 1,25(OH)2D3 appeared to decrease steady state c-myc mRNA levels by increasing its turnover rate. Using actinomycin D to block transcription, the half-life of c-myc mRNA was shown to decrease from 20 min in the absence of 1,25(OH)2D3 to < 5 min in the presence of 1,25(OH)2D3. Cycloheximide reversed the instability induced by 1,25(OH)2D3, prolonging the half-life of c-myc mRNA in both uninduced and 1,25(OH)2D3-induced HL-60 cells to > 60 min, indicating a translational requirement for the destabilization process. Additionally, the c-myc mRNA instability induced by 1,25(OH)2D3 in HL-60 appears to be a specific result of this agent, as indicated by the inability of other monocytic and granulocytic differentiation inducing agents to destabilize c-myc mRNA.