Antimitogenic effects of dexamethasone in chemically transformed mouse fibroblasts.
Dexamethasone (a synthetic glucocorticoid) inhibited the entry into the S-phase of quiescent chemically transformed mouse fibroblasts (BP-A31) stimulated with 12-O-tetradecanoyl 13-acetate (TPA; a protein kinase-C activator) or with basic fibroblast growth factor. The basal rate of DNA synthesis was also strongly reduced by dexamethasone. In contrast, the mitogenic activity of insulin (acting via the insulin-like growth factor-I receptor) was little or not at all affected by dexamethasone. The antimitogenic activity of dexamethasone was enhanced when the steroid was included in the culture medium 24 h before the addition of mitogens. The effects of dexamethasone were glucocorticoid specific, partially reversed by the antiglucocorticoid RU 486, and prevented by cycloheximide (suggesting the involvement of glucocorticoid-induced protein synthesis in the antimitogenic activity of dexamethasone). Under the conditions of exponential growth in serum-free medium as well as in the presence of TPA, dexamethasone arrested the proliferation of sparsely seeded cells after a delay of 24-48 h. The BP-A31 cells are known to be constitutively competent and express at quiescence certain genes related to the G0/G1 transition in the original nontransformed A31 cell line. Of the transcripts corresponding to these genes, dexamethasone caused a rapid elimination of the JE mRNA, coding for a protein of the family of cytokines. The cell content of c-jun mRNA was also strongly reduced in the cells incubated at quiescence with dexamethasone (in the absence of mitogen). The presence of TPA along with dexamethasone prevented the elimination of c-jun, but not of JE mRNA. Short (30-min; together with the inducers) or long (24-h) treatment of the cells with dexamethasone did not prevent the induction of the c-fos gene expression by either TPA or basic fibroblast growth factor, indicating that dexamethasone does not interfere with mitogenic signal transduction. We conclude that in TPA-stimulated cells, the antiproliferative effect of dexamethasone is not due to interference with the expression of the c-jun gene, but may be related to the decreased level of the JE cytokine mRNA as well as to the synthesis of growth inhibitory protein(s).
Fagot
D
D
INSERM U.55, Paris, France.
Buquet-Fagot
C
C
Mester
J
J
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D018932:Chemokine CCL2; D002630:Chemotactic Factors / Q000235:genetics; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics
D018932:Chemokine CCL2; D002630:Chemotactic Factors; D004268:DNA-Binding Proteins; D007328:Insulin; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D015735:Mifepristone; D003907:Dexamethasone; D004247:DNA; D003513:Cycloheximide; D013755:Tetradecanoylphorbol Acetate