Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the extracellular-regulated kinases in human cultured airway smooth muscle
Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the extracellular-regulated kinases in human cultured airway smooth muscle
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DOI：
10.1165/ajrcmb.21.1.3396
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发表时间：
1999-07-01
影响因子：
6.4
通讯作者：
Stewart, AG
中科院分区：
文献类型：
--
作者：
Fernandes, D;Guida, E;Stewart, AG
我们之前已经证明，糖皮质激素可以抑制人培养的气道平滑肌（ASM）细胞的有丝分裂原刺激的增殖。本研究分析了糖皮质激素对导致细胞通过细胞周期限制点的关键调控途径的影响，包括由细胞外调节激酶 (ERK) 1 和 2 介导的途径； ERK 上游调节器 MAPK 激酶 (MEK1)；细胞周期蛋白 D1 水平；视网膜母细胞瘤蛋白 (pRb) 的水平和磷酸化。丙酸氟替卡松是一种新型吸入性糖皮质激素，在抑制凝血酶刺激的 DNA 合成和细胞数量增加方面，其效力至少比地塞米松强 10 倍。糖皮质激素可抑制凝血酶刺激的 pRb 水平升高和过度磷酸化，从而降低凝血酶刺激的细胞周期蛋白 D1 蛋白和信使 RNA (mRNA) 水平。 PD98059 (10 mu M) 是一种 MEK1 激活抑制剂，可显着减弱凝血酶对 ERK 活性和磷酸化、DNA 合成和细胞周期蛋白 D1 水平的刺激。然而，在添加凝血酶后5分钟、2小时或12小时，糖皮质激素对ERK活性或磷酸化没有影响。总之，糖皮质激素诱导的细胞周期蛋白 D1 mRNA 和蛋白水平以及 pRb 磷酸化的降低足以解释 ASM 增殖的抑制。此外，糖皮质激素对细胞周期蛋白 D1 和 pRb 的这些抑制作用发生在有丝分裂原信号级联的一个组件上，该组件位于 ERK 通路的下游或平行于 ERK 通路。
We have previously shown that glucocorticoids inhibit mitogen-stimulated proliferation of human cultured airway smooth muscle (ASM) cells. The present study analyzed the effect of glucocorticoids on key regulatory pathways leading to passage of cells through the restriction point of the cell cycle, including those mediated by extracellular-regulated kinases (ERK) 1 and 2; the ERK upstream regulator MAPK kinase (MEK1); cyclin D1 levels; and levels and phosphorylation of retinoblastoma protein (pRb). Fluticasone propionate, a new inhaled glucocorticoid, was at least 10-fold more potent than dexamethasone in inhibiting thrombin-stimulated DNA synthesis and increases in cell number. Thrombin-stimulated increases in the levels and hyperphosphorylation of pRb were inhibited by glucocorticoids, which also reduced thrombin-stimulated cyclin D1 protein and messenger RNA (mRNA) levels. PD98059 (10 mu M), an inhibitor of MEK1 activation, markedly attenuated thrombin stimulation of ERK activity and phosphorylation, DNA synthesis, and cyclin D1 levels. However, glucocorticoids had no effect on ERK activity or phosphorylation at 5 min, 2 h, or 12 h after addition of thrombin. In conclusion, glucocorticoid-induced reduction of cyclin D1 mRNA and protein levels, and of pRb phosphorylation, is sufficient to account for inhibition of ASM proliferation. Furthermore, these inhibitory effects of glucocorticoids on cyclin D1 and pRb occur on a component of the mitogen signaling cascade that is either downstream of or parallel to the ERK pathway.