Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor γ during bone morphogenetic protein 2-induced adipogenesis
Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor γ during bone morphogenetic protein 2-induced adipogenesis
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DOI：
10.1091/mbc.e02-06-0356
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发表时间：
2003-02-01
影响因子：
3.3
通讯作者：
Yoneda, T
中科院分区：
文献类型：
--
作者：
Hata, K;Nishimura, R;Yoneda, T
骨形态发生蛋白 2 (BMP2) 促进未分化间充质细胞分化为脂肪细胞。为了研究调节这一分化过程的分子机制，我们利用多能间充质细胞系 C3H10T1/2 研究了间充质细胞脂肪形成过程中 BMP2 信号传导与过氧化物酶体增殖物激活受体 γ (PPAR-y) 之间的关系。在 C3H10T1/2 细胞中，BMP2 诱导 PPARγ 表达以及脂肪生成。 Smad6（Smad1 的天然拮抗剂）的过度表达可阻断 PPAR-y 表达和 BMP2 诱导的脂肪细胞分化。显性失活 PPARγ 的过度表达也减少了 C3H10T1/2 细胞的脂肪细胞分化，表明 PPARgamma 在 BMP2 诱导的脂肪细胞分化中发挥着核心作用。 p38激酶的特异性抑制剂抑制BMP2诱导的脂肪细胞分化和PPARγ的转录激活，而Smad6的过表达对PPARγ的转录活性没有影响。此外，通过TAK1和TAB1的过度表达激活p38激酶，在不影响PPARγ表达的情况下，导致PPARγ转录活性的上调。这些结果表明，Smad 和 p38 激酶信号传导同时激活，并分别通过诱导和上调 PPARgamma 来负责 BMP2 诱导的脂肪细胞分化。因此，BMP2 通过使用两种不同的信号通路来控制脂肪细胞分化，这两种信号通路在 C3H10T1/2 细胞的这一过程中发挥不同的作用。
Bone morphogenetic protein 2 (BMP2) promotes the differentiation of undifferentiated mesenchymal cells into adipocytes. To investigate the molecular mechanisms that regulate this differentiation process, we studied the relationship between BMP2 signaling and peroxisome proliferator-activating receptor gamma (PPAR-y) during adipogenesis of mesenchymal cells by using pluripotent mesenchymal cell line C3H10T1/2. In C3H10T1/2 cells, BMP2 induced expression of PPARy along with adipogenesis. Overexpression of Smad6, a natural antagonist for Smad1, blocked PPAR-y expression and adipocytic differentiation induced by BMP2. Overexpression of dominant-negative PPARy also diminished adipocytic differentiation of C3H10T1/2 cells, suggesting the central role of PPARgamma in BMP2-induced adipocytic differentiation. Specific inhibitors for p38 kinase inhibited BMP2-induced adipocytic differentiation and transcriptional activation of PPARgamma, whereas overexpression of Smad6 had no effect on transcriptional activity of PPARgamma. Furthermore, activation of p38 kinase by overexpression of TAK1 and TAB1, without affecting PPARgamma expression, led the up-regulation of transcriptional activity of PPARgamma. These results suggest that both Smad and p38 kinase signaling are concomitantly activated and responsible for BMP2-induced adipocytic differentiation by inducing and up-regulating PPARgamma, respectively. Thus, BMP2 controls adipocytic differentiation by using two distinct signaling pathways that play differential roles in this process in C3H10T1/2 cells.