p38 Regulates Expression of Osteoblast-specific Genes by Phosphorylation of Osterix
p38 Regulates Expression of Osteoblast-specific Genes by Phosphorylation of Osterix
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DOI：
10.1074/jbc.m110.123612
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发表时间：
2010-10-15
影响因子：
4.8
通讯作者：
Ventura, Francesc
中科院分区：
文献类型：
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作者：
Jose Ortuno, Maria;Ruiz-Gaspa, Silvia;Ventura, Francesc
Osterix是一种锌指转录因子，在所有发育中的骨的成骨细胞和骨细胞中特异性表达。由于osx缺失小鼠不发生骨形成，因此Osterix被认为是成骨细胞分化的重要调节剂。我们报道，在几种间充质细胞和成骨细胞类型中，BMP-2诱导Osterix的两种异构体的表达增加，这两种异构体是由两种不同的启动子引起的。在体外和体内实验中，我们一致发现Sp1序列（gggggg）是纤维调节蛋白和骨唾液蛋白启动子中的Osterix结合区。此外，我们发现Osterix在体内和体外都是p38 MAPK的新底物，Ser-73和Ser-77是p38磷酸化的调控位点。我们的数据还表明，Osterix能够在体内增加p300和Brg1对其靶基因纤维调节蛋白和骨唾液蛋白启动子的募集，并通过蛋白-蛋白相互作用与这些辅助因子直接相关。Osterix Ser-73/77位点的磷酸化增加了其募集p300和SWI/SNF到纤维调节蛋白或骨唾液蛋白启动子的能力。因此，我们提出Osterix与靶基因启动子上的Sp1序列结合，p38对其的磷酸化增强了共激活子的募集，形成转录活性复合物。
Osterix, a zinc finger transcription factor, is specifically expressed in osteoblasts and osteocytes of all developing bones. Because no bone formation occurs in Osx-null mice, Osterix is thought to be an essential regulator of osteoblast differentiation. We report that, in several mesenchymal and osteoblastic cell types, BMP-2 induces an increase in expression of the two isoforms of Osterix arising from two alternative promoters. We identified a consensus Sp1 sequence (GGGCGG) as Osterix binding regions in the fibromodulin and the bone sialoprotein promoters in vitro and in vivo. Furthermore, we show that Osterix is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-73 and Ser-77 are the regulatory sites phosphorylated by p38. Our data also demonstrate that Osterix is able to increase recruitment of p300 and Brg1 to the promoters of its target genes fibromodulin and bone sialoprotein in vivo and that it directly associates with these cofactors through protein-protein interactions. Phosphorylation of Osterix at Ser-73/77 increased its ability to recruit p300 and SWI/SNF to either fibromodulin or bone sialoprotein promoters. We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes.