Bre Enhances Osteoblastic Differentiation by Promoting the Mdm2-Mediated Degradation of p53
Bre Enhances Osteoblastic Differentiation by Promoting the Mdm2-Mediated Degradation of p53
复制标题
Bre 通过促进 Mdm2 介导的 p53 降解来增强成骨细胞分化
DOI：
10.1002/stem.2620
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发表时间：
2017-07-01
期刊：
影响因子：
5.2
通讯作者：
Wang, Yifei
中科院分区：
文献类型：
--
作者：
Jin, Fujun;Wang, Yiliang;Wang, Yifei
Bre是一种在多种组织中表达的保守的细胞蛋白。其主要功能包括DNA损伤修复和抗凋亡。最近的研究表明，Bre可能参与干细胞的分化，但其病理生理意义沿着分子机制仍不清楚。在这里，我们报告说，Bre蛋白基本上在骨组织中表达，其表达在成骨分化过程中高度上调。为了验证Bre在成骨分化过程中发挥功能作用的假设，我们检测了Bre在骨质疏松症小鼠模型中的表达。与正常骨组织相比，增生骨组织中Bre的表达也明显减少。此外，敲低Bre基因可显著降低小鼠骨髓间充质细胞成骨标志基因的表达、碱性磷酸酶活性和矿化能力，而过表达Bre基因可显著促进体内外成骨。有趣的是，我们发现Bre的敲低导致p53信号通路的激活，表现为p53，p21和Mdm 2的增加。然而，当我们通过siRNA沉默或pifithrin-z抑制p53时，由Bre敲低引起的受损的骨生成得到了极大的恢复。最后，我们发现Bre通过与p53物理相互作用促进Mdm 2介导的p53泛素化和降解。综上所述，我们的研究结果揭示了Bre通过调节p53的稳定性在成骨细胞分化中的新功能。
Bre is a conserved cellular protein expressed in various tissues. Its major function includes DNA damage repair and anti-apoptosis. Recent studies indicate that Bre is potentially involved in stem cell differentiation although pathophysiological significance along with the molecular mechanisms is still unclear. Here, we report that Bre protein was substantially expressed in the bone tissue and its expression was highly upregulated during the osteogenic differentiation. To test a hypothesis that Bre plays functional roles in the process of osteogenic differentiation, we examined the expression of Bre in an osteoporosis mouse model. Compared with the normal bone tissue, Bre expression in osteoporotic bone was also significantly reduced. Moreover, knockdown of Bre in the mouse bone marrow mesenchymal cells significantly reduced the expression of osteogenic marker genes, the alkaline phosphatase activity, and the mineralization capacity, while overexpression of Bre greatly promoted the osteogenesis both in vitro and in vivo. Interestingly, we founded that knockdown of Bre led to activation of the p53 signaling pathways exhibited by increased p53, p21, and Mdm2. However, when we inhibited the p53 by siRNA silencing or pifithrin-z the impaired osteogenesis caused by Bre knockdown was greatly restored. Finally, we found that Bre promoted the Mdm2-mediated p53 ubiquitination and degradation by physically interacting with p53. Taken together, our results revealed a novel function of Bre in osteoblast differentiation through modulating the stability of p53.