SYNERGISTIC INCREASE OF PHORBOL ESTER-INDUCED C-FOS MESSENGER-RNA EXPRESSION BY RETINOIC ACID THROUGH STABILIZATION OF THE C-FOS MESSAGE

Retinoic acid (RA) has been shown to be able to antagonize or synergiz e with phorbol 12-myristate 13-acetate (PMA). In contrast to its antag onistic effects on PMA-dependent gene expression, no molecular target or mechanism of synergism has been characterized yet. We now report, t hat RA synergistically enhances the induction of c-fos, but not c-jun mRNA by PMA in cells whose growth was stimulated by RA alone. The resp onding cells were hybrids of tumor cell lines whose growth and PMA-dep endent c-fos mRNA expression remained unaffected by RA. The increase i n PMA-dependent c-fos expression required pretreatment of cells with R A for at least 2 - 4 h and was achieved at doses as low as 10(-10) M. Nuclear run-on experiments and transient transfection assays using a c himeric reporter gene construct with sequences from the c-fos promoter indicated that RA did not affect PMA-dependent c-fos transcription. I nstead, RA stabilized the c-fos message after induction by PMA as asse ssed by measuring the half-life of c-fos mRNA in actinomycin D-treated cells. This post-transcriptional regulation provides a mechanism wher eby RA can synergistically enhance gene expression by PMA.