Bone morphogenetic protein 2-induced osteoblast differentiation requires smad-mediated down-regulation of Cdk6
Bone morphogenetic protein 2-induced osteoblast differentiation requires smad-mediated down-regulation of Cdk6
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DOI：
10.1128/mcb.24.15.6560-6568.2004
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发表时间：
2004-08-01
影响因子：
5.3
通讯作者：
Okayama, H
中科院分区：
文献类型：
--
作者：
Ogasawara, T;Kawaguchi, H;Okayama, H
由于细胞周期的 G 期暂时停滞被认为是细胞分化的先决条件，因此我们研究了对骨形态发生蛋白 2 (BMP-2)（一种成骨细胞分化的有效诱导剂）诱导的小鼠成骨细胞 MC3T3-E1 细胞分化有重要影响的细胞周期因素。在检查的 G 细胞周期因子中，发现细胞周期蛋白依赖性激酶 6 (Cdk6) 的表达受到 BMP-2/Smads 信号传导的强烈下调，主要是通过转录抑制。 Cdk6 的强制表达在不同程度上阻断了 BMP-2 诱导的成骨细胞分化，具体取决于其过表达的水平。然而，BMP-2处理和Cdk6过表达均未显着影响细胞增殖，这表明Cdk6对细胞分化的抑制作用是通过一种很大程度上独立于其细胞周期调节的机制发挥的。这些结果表明，Cdk6 是 BMP-2 诱导的成骨细胞分化的关键调节因子，并且其 Smads 介导的下调对于有效的成骨细胞分化至关重要。
Because a temporal arrest in the G, phase of the cell cycle is thought to be a prerequisite for cell differentiation, we investigated cell cycle factors that critically influence the differentiation of mouse osteoblastic MC3T3-E1 cells induced by bone morphogenetic protein 2 (BMP-2), a potent inducer of osteoblast differentiation. Of the G, cell cycle factors examined, the expression of cyclin-dependent kinase 6 (Cdk6) was found to be strongly down-regulated by BMP-2/Smads signaling, mainly via transcriptional repression. The enforced expression of Cdk6 blocked BMP-2-induced osteoblast differentiation to various degrees, depending on the level of its overexpression. However, neither BMP-2 treatment nor Cdk6 overexpression significantly affected cell proliferation, suggesting that the inhibitory effect of Cdk6 on cell differentiation was exerted by a mechanism that is largely independent of its cell cycle regulation. These results indicate that Cdk6 is a critical regulator of BMP-2-induced osteoblast differentiation and that its Smads-mediated down-regulation is essential for efficient osteoblast differentiation.