Expression of p27(Kip1) in osteoblast-like cells during differentiation with parathyroid hormone
Expression of p27(Kip1) in osteoblast-like cells during differentiation with parathyroid hormone
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DOI：
10.1210/en.138.5.1995
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发表时间：
1997-05-01
期刊：
影响因子：
4.8
通讯作者：
Hruska, K
中科院分区：
文献类型：
--
作者：
Onishi, T;Hruska, K
PTH 是骨代谢的主要全身调节剂，在骨形成和骨吸收中发挥重要作用。 PTH 会抑制或刺激成骨细胞增殖，具体取决于所研究的模型。我们分析了 UMR-106 细胞系的细胞周期，该细胞系是一种相对分化的成骨细胞成骨肉瘤系，已知 PTH 可以抑制增殖，但作用机制尚不清楚。 PTH降低S期细胞比例，增加G1期细胞数量。我们检查了 PTH 对 G1 期细胞周期蛋白依赖性激酶调节因子的影响，发现 PTH 增加了 p27 (Kip1) 水平，但不增加 p21 (Kip1) 水平。 8-溴-cAMP 可以模拟这种效应，但佛波醇 12-肉豆蔻酸酯 13-乙酸酯不能模拟这种效应。蛋白激酶A抑制剂KT5720消除了PTH对p27(Kip1)表达增加的影响。 PTH 增加 CDK2 相关的 p27(Kip1)，而不影响 CDK2 的水平。 PTH 和 8-bromo-cAMP 治疗均下调 CDK2 活性。这些数据表明PTH阻止细胞进入8期并抑制细胞。 p27(Kip1) 增加导致增殖，这是通过蛋白激酶 A 途径介导的。 p27(Kip1) 对 G1 细胞周期蛋白依赖性激酶的抑制可能导致关键底物磷酸化减少和进入 S 期必需的转录因子失活。通过 PKA 介导的 p27（Kip1）诱导抑制细胞周期进程可能在 PTH 诱导的成骨细胞分化中发挥重要作用。
PTH is a major systemic regulator of bone metabolism and plays an important role in both bone formation and resorption. PTH either inhibits or stimulates osteoblastic cell proliferation depending on the model that is studied. We analyzed the cell cycle of the UMR-106 cell line, a relatively differentiated osteoblastic osteogenic sarcoma line in which PTH is known to inhibit proliferation but the mechanism of action is unknown. PTH decreased the proportion of cells in S phase and increased the number of G1 phase cells. We examined the effect of PTH on the regulators of the G1 phase cyclin-dependent kinases and found that PTH increased p27(Kip1), but not p21(Kip1), levels. This effect was mimicked by 8-bromo-cAMP, but not by phorbol 12-myristate 13-acetate. The protein kinase A inhibitor KT5720 abolished the effect of PTH on the increase in p27(Kip1) expression. PTH increased CDK2-associated p27(Kip1) without affecting the levels of CDK2. CDK2 activity was down-regulated by both PTH and 8-bromo-cAMP treatment. These data suggest that PTH blocks entry of cells into 8 phase and inhibits cell. proliferation as the consequence of an increase in p27(Kip1), which is mediated through the protein kinase A pathway. The inhibition of G1 cyclin-dependent kinases by p27(Kip1) could cause a reduction of phosphorylation of key substrates and inactivation of transcription factors essential for entry into S phase. The inhibition of cell cycle progression through PKA-mediated p27(Kip1) induction might play an important role in PTH-induced differentiation of osteoblasts.