title: Posttranscriptional regulation of colony-stimulating factor-1 (CSF-1) and CSF-1 receptor gene expression during inhibition of phorbol-ester-induced monocytic differentiation by dexamethasone and cyclosporin A: potential involvement of a destabilizing protein.
abstract: Colony stimulating factor-1 (CSF-1) and its receptor (encoded by the c-fms proto-oncogene) have long been recognized as playing an important role in monocytic differentiation. However, the regulation of expression of the CSF-1 and c-fms genes during inhibition of monocytic differentiation has not been fully characterized. The present studies demonstrate that dexamethasone (dex) and cyclosporin A (CsA) resulted in inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced monocytic differentiation of HL60 cells, as well as TPA induction of c-fms and CSF-1 transcripts. These agents also blocked TPA-induced adherence, alpha-naphthyl acetate esterase staining, and the development of a more differentiated morphology. Nuclear run-off analyses revealed no effect of either of these agents on transcription of either c-fms or CSF-1 genes in TPA-treated HL60 cells. Measurements of c-fms transcript half-life confirmed post-transcriptional regulation of c-fms transcript levels after the addition of dex or CsA to TPA, both of which resulted in a decrease in c-fms mRNA half-life. Others have suggested that TPA results in the stabilization of c-fms mRNA in HL60 cells through induction of a labile mRNA stabilizing protein. We observed, however, that the inhibition of protein synthesis by cycloheximide (CH) in this setting of early monocytic differentiation increased both c-fms and CSF-1 steady-state transcript levels. While CH had no effect on the transcription of c-fms and CSF-1 genes in TPA/dex- or TPA/CsA-treated HL60 cells, c-fms mRNA was stabilized after the addition of CH to TPA/dex-treated cells. Taken together, our results suggest the existence of a labile mRNA regulatory protein or proteins, whose actions include destabilization of both c-fms and CSF-1 transcripts after inhibition of TPA-induced monocytic differentiation by dex or CsA.
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: S K
authors.initials: SK
authors.lastname: Chambers
authors.forename: M
authors.initials: M
authors.lastname: Gilmore-Hebert
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Rodov
authors.forename: E J
authors.initials: EJ
authors.lastname: Benz
authors.forename: B M
authors.initials: BM
authors.lastname: Kacinski
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D009000:Monocytes / Q000166:cytology*; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor; D016572:Cyclosporine; D003513:Cycloheximide; D016186:Receptor, Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate