Multiple calcium-mediated mechanisms regulate c-myc expression in HL-60 cells

Treatment of human promyelocytic leukemia cells (HL-60) with the calcium ionophore A23187 induced a biphasic change in the expression of the c-myc protooncogene. Within 1 h of exposure to a single 2.5-microM dose of A23187, steady state levels of c-myc mRNA increased to 170% of control. After this early increase, c-myc mRNA expression underwent an abrupt decline over the next 2 to 4 h. Between 6 to 18 h of treatment with A23107, steady state levels of c-myc mRNA fell gradually toward zero. The early increase in expression of c-myc mRNA was mediated by both enhanced initiation of c-myc transcription and posttranscriptional stabilization of c-myc mRNA. Stimulation of HL-60 cells with A23187 for 30 min increased transcription of both exons 1 and 3 of c-myc by 125%. After 1 h of treatment with A23187, the half-life of c-myc mRNA increased to 150% of control. The late decrease in c-myc expression induced by A23187 was primarily mediated by interruption of elongation of c-myc nascent mRNA beyond exon 1. The combination of calcium ionophore A23187 and phorbol 12,13-dibutyrate acted synergistically to inhibit expression of c-myc mRNA.