Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix
Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix
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DOI：
10.1016/j.bone.2015.02.026
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发表时间：
2015-06-01
期刊：
影响因子：
4.1
通讯作者：
Lee, Kwang Youl
中科院分区：
文献类型：
--
作者：
Choi, You Hee;Han, Younho;Lee, Kwang Youl
E3泛素连接酶Cbl-b和c-Cbl在骨形成和维持中发挥重要作用。Cbl-b和c-Cbl主要通过调节靶蛋白的降解来调节各种受体酪氨酸激酶和细胞内蛋白酪氨酸激酶的活性。然而，Cbl-b和c-Cbl调控成骨细胞分化的确切机制还不是很清楚。在本研究中，我们研究了Cbl-b和c-Cbl的潜在靶标。我们发现Cbl-b和c-Cbl抑制BMP2诱导的间充质细胞向成骨细胞分化。在众多成骨转录因子中，我们发现Cbl-b和c-Cbl抑制Osterix的蛋白质稳定性和转录活性。我们的结果表明，Cbl-b和c-Cbl通过促进泛素蛋白酶体介导的Osterix的降解而抑制Osterix的功能。综上所述，我们提出了Cbl-b和c-Cbl在成骨细胞分化过程中的新的调控作用，其中Cbl-b和c-Cbl通过泛素-蛋白酶体途径调节Osterix的降解。(C)2015 Elsevier Inc.保留所有权利。
E3 ubiquitin ligase Cbl-b and c-Cbl play important roles in bone formation and maintenance. Cbl-b and c-Cbl regulate the activity of various receptor tyrosine kinases and intracellular protein tyrosine kinases mainly by regulating the degradation of target proteins. However, the precise mechanisms of how Cbl-b and c-Cbl regulate osteoblast differentiation are not well known. In this study, we investigated potential targets of Cbl-b and c-Cbl. We found that Cbl-b and c-Cbl inhibit BMP2-induced osteoblast differentiation in mesenchymal cells. Among various osteogenic transcription factors, we identified that Cbl-b and c-Cbl suppress the protein stability and transcriptional activity of Osterix. Our results suggest that Cbl-b and c-Cbl inhibit the function of Osterix by enhancing the ubiquitin-proteasome-mediated degradation of Osterix. Taken together, we propose novel regulatory roles of Cbl-b and c-Cbl during osteoblast differentiation in which Cbl-b and c-Cbl regulate the degradation of Osterix through the ubiquitin-proteasome pathway. (C) 2015 Elsevier Inc. All rights reserved.