POSTTRANSCRIPTIONAL REGULATION OF COLONY-STIMULATING FACTOR-I (CSF-1)AND CSF-1 RECEPTOR GENE-EXPRESSION DURING INHIBITION OF PHORBOLESTER-INDUCED MONOCYTIC DIFFERENTIATION BY DEXAMETHASONE AND CYCLOSPORINE-A - POTENTIAL INVOLVEMENT OF A DESTABILIZING PROTEIN

Colony stimulating factor-1 (CSF-1) and its receptor (encoded by the c -fins proto-oncogene) have long been recognized as playing an importan t role in monocytic differentiation. However, the regulation of expres sion of the CSF-1 and c-fins genes during inhibition of monocytic diff erentiation has not been fully characterized. The present studies demo nstrate that dexamethasone (dex) and cyclosporin A (CsA) resulted in i nhibition of 12-0-tetladecanoylphorbol-13-acetate (TPA)-induced monocy tic differentiation of HL60 cells, as well as TPA induction of c-fms a nd CSF-1 transcripts. These agents also blocked TPA-induced adherence, a-naphthyl acetate esterase staining, and the development of a more d ifferentiated morphology. Nuclear run-off analyses revealed no effect of either of these agents on transcription of either c-fms or CSF-1 ge nes in TPA-treated HL60 cells. Measurements of c-fins transcript half- life confirmed posttranscriptional regulation of c-fins transcript lev els after the addition of dex or CsA to TPA, both of which resulted in a decrease in c-fins mRNA half-life. Others have suggested that TPA r esults in the stabilization of c-fins mRNA in HL60 cells through induc tion of a labile mRNA stabilizing protein. We observed, however, that the inhibition of protein synthesis by cycloheximide (CH) in this sett ing of early monocytic differentiation increased both c-fms and CSF-1 steady-state transcript levels. While CH had no effect on the transcri ption of c-fins and CSF-1 genes in TPA/dex- or TPA/CsA-treated HL60 ce lls, c-fins mRNA was stabilized after the addition of CH to TPA/dex-tr eated cells. Taken together, our results suggest the existence of a la bile mRNA regulatory protein or proteins, whose actions include destab ilization of both c-fins and CSF-1 transcripts after inhibition of TPA -induced monocytic differentiation by dex or CsA.