Involvement of Two Intracellular Messenger Systems, Protein Kinase C and Cyclic AMP, in the Regulation of c-fos Gene Expression in Human Promyelocytic Leukemia (HL-60) Cells1

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Abstract
Incubation of human promyelocytic leukemia (HL-60) cells with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a protein kinase C-activating phorbol ester, caused a marked increase in c-fos mRNA in a dose-dependent manner. Phorbol-12,13-dibutyrate and l-oleoyl-2-acetyl-glycerol, other protein kinase C-activating agents, were also active in this capacity. 4α-Phorbol-12,13-didecanoate, known to be inactive for protein kinase C, was ineffective. 8-Bromo-cyclic AMP (8-Br-cAMP) also increased c-fos mRNA in a dose-dependent manner. This action of 8-Br-cAMP was mimicked by prostaglandin E2, which is known to raise the cyclic AMP level in HL-60 cells, c-fos mRNA increased within 15 min and reached a maximal level 45 min after the stimulation of the cells by TPA or 8-Br-cAMP. The simultaneous stimulation of the cells by TPA and 8-Br-cAMP at the respective doses giving maximal elevation of c-fos mRNA increased this mRNA in an additive manner. These results suggest that in HL-60 cells expression of the c-fos gene is regulated independently by two different intracellular messenger systems, protein kinase C and cyclic AMP.