1,25-Dihydroxyvitamin D-3 destabilizes c-myc mRNA 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.
Mangasarian
K
K
School of Pharmacy, University of Wisconsin, Madison 53706.
Mellon
W S
WS
D015152:Blotting, Northern; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D003850:Deoxyribonuclease I; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D015183:Restriction Mapping; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D003850:Deoxyribonuclease I; D002117:Calcitriol