DITHIOCARBAMATES TRIGGER DIFFERENTIATION AND INDUCTION OF CD11C GENE THROUGH AP-1 IN THE MYELOID LINEAGE

It has recently been shown that the alteration of the cell-redox statu s affects the transcription factor expression and activity. Dithiocarb amates (DTCs) are potent antioxidant agents that can switch the expres sion of genes dependent on the activation of the transcription factors AP-1 and NF kappa B. In this study, we show that these agents trigger ed the expression of genes involved in myeloid differentiation of the promonocytic U-937 cell line. DTCs promoted differentiation-associated changes that included the surface up-regulation of pa-integrins (CD11 a-c/CD18), cell growth arrest concomitant with transferrin receptor (C D71) down modulation, induction of the nonspecific esterase enzyme, an d a rapid drop in the mRNA levels of c-myc. A further analysis, focuse d on the molecular mechanisms leading 60 the activation of CD11c expre ssion, revealed that the pyrrolidine derivative of DTC (PDTC) increase d CD11c mRNA levels and augmented its gene promoter activity. Transfec tion experiments with reporter constructs harboring different promoter regions of CD11c gene, indicated the presence of a functional DTC-res ponsive region located between positions -160 and +40 of the promoter. Gel retardation assays revealed that the PDTC-induced DNA-protein com plexes were restricted to members of the Fos and Jun families that bou nd to an AP-1 site located at position -60 from the transcription star t site. A role for this site was confirmed by in vitro mutagenesis exp eriments that indicated the functional importance of this site for the CD11c gene transcriptional activation in response to PDTC. The effect of DTCs on myeloid cell differentiation supports a possible role for these agents in the therapy of some bone marrow-derived malignancies.