Fagot D, Buquet-Fagot C, Mester J
INSERM U.55, Paris, France.
Endocrinology. 1991 Aug;129(2):1033-41. doi: 10.1210/endo-129-2-1033.
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).
地塞米松（一种合成糖皮质激素）可抑制经12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA；一种蛋白激酶 - C激活剂）或碱性成纤维细胞生长因子刺激的静止化学转化小鼠成纤维细胞（BP - A31）进入S期。地塞米松还能显著降低DNA合成的基础速率。相比之下，胰岛素（通过胰岛素样生长因子 - I受体发挥作用）的促有丝分裂活性几乎不受地塞米松影响或完全不受影响。当在添加促有丝分裂原前24小时将该类固醇加入培养基中时，地塞米松的抗有丝分裂活性增强。地塞米松的作用具有糖皮质激素特异性，可被抗糖皮质激素RU 486部分逆转，并被环己酰亚胺阻止（提示糖皮质激素诱导的蛋白质合成参与了地塞米松的抗有丝分裂活性）。在无血清培养基中指数生长以及存在TPA的条件下，地塞米松在延迟24 - 48小时后使稀疏接种的细胞增殖停滞。已知BP - A31细胞具有组成型能力，并且在静止状态下表达与原始未转化A31细胞系中G0/G1转变相关的某些基因。在与这些基因对应的转录本中，地塞米松导致编码细胞因子家族一种蛋白质的JE mRNA迅速消除。在静止状态下用地塞米松培养的细胞（在无促有丝分裂原的情况下）中，c - jun mRNA的细胞含量也显著降低。TPA与地塞米松共同存在可阻止c - jun的消除，但不能阻止JE mRNA的消除。用地塞米松对细胞进行短时间（30分钟；与诱导剂一起）或长时间（24小时）处理，均不能阻止TPA或碱性成纤维细胞生长因子诱导c - fos基因表达，这表明地塞米松不干扰促有丝分裂信号转导。我们得出结论，在TPA刺激的细胞中，地塞米松的抗增殖作用并非由于干扰c - jun基因的表达，而是可能与JE细胞因子mRNA水平降低以及生长抑制蛋白的合成有关。
