Dioctanoylglycerol and phorbol esters regulate transcription of c-myc in human promyelocytic leukemia cells

Abstract

Treatment of human promyelocytic leukemia cells (HL-60) with phorbol 12-myristate 13-acetate or phorbol 12,13-dibutyrate (PDBu) caused a rapid decrease in transcription of the c-myc protooncogene. In the continuous presence of PMA or PDBu, the rate of transcription of c-myc decreased to 20% of control within 2 h and was maintained at 20-30% of the control level for the ensuing 24 h. Cell-permeable sn-1,2-dioctanoylglycerol (diC8), a diacylglycerol analogue, also caused a rapid decrease in c-myc transcription. The decrease in the transcription of c-myc induced by diC8 or PDBu was reversible; prolonged exposure of the cells to either agent for periods greater than 2 h was necessary to maintain the transcription of c-myc below the control rate. With both PDBu and diC8, there was a close correlation between the concentration dependence for binding to the phorbol ester receptor and the concentration dependence for inhibition of c-myc transcription. The decrease in transcription of c-myc induced by PDBu or diC8 appeared to be due to a block of elongation of the nascent mRNA beyond exon 1. The results of this study suggest that prolonged stimulation of protein kinase C (Ca2+/phospholipid-dependent enzyme) is required for persistent inhibition of transcription of c-myc in HL-60 cells.