The interferon-inducible p204 protein acts as a transcriptional coactivator of Cbfa1 and enhances osteoblast differentiation
The interferon-inducible p204 protein acts as a transcriptional coactivator of Cbfa1 and enhances osteoblast differentiation
复制标题
DOI：
10.1074/jbc.m412604200
复制
发表时间：
2005-01-28
影响因子：
4.8
通讯作者：
Di Cesare, PE
中科院分区：
文献类型：
--
作者：
Liu, CJ;Chang, E;Di Cesare, PE
间充质细胞向成骨细胞的分化是控制胚胎发育和骨修复的基本分子事件。骨形态发生蛋白（BMPs）是这一过程的重要调节因子;它们通过与细胞表面受体结合并通过Smad蛋白进行信号传导来发挥作用。核心结合因子α 1（core binding factor alpha-1，Cbfa 1）是转录因子runt家族的一员，是成骨细胞分化和骨形成的重要转录调节因子，该过程受多种辅激活因子和辅抑制因子的正或负调控。我们报告说，p204，干扰素诱导蛋白，以前被证明可以抑制细胞增殖，促进成肌细胞分化成肌管，是一种新的调节剂在成骨过程中。p204在胚胎成骨细胞和生长板中的肥大软骨细胞以及新生小鼠的头盖骨成骨细胞中表达。其水平在BMP-2触发的多能C2 C12细胞的成骨细胞分化过程中增加。这种增加可能是由于编码204（Ifi 2 O 4）的基因被Smad转录因子（包括Smad 1、-4和-5）激活。p204的过表达增强BMP-2诱导的成骨细胞分化在体外，如所揭示的升高的碱性磷酸酶活性和骨钙素的生产。p204作为Cbfa 1的辅因子：1）p204高水平表达增强Cbfa 1依赖性转录，而p204低水平表达减弱Cbfa 1依赖性转录; 2）p204与Cbfa 1在体外和体内均存在相关性。p204中的两个非重叠片段与Cbfa 1结合，Cbfa 1的N-末端88个氨基酸片段是与p204结合所必需的。p204是第一个发现与Cbfa 1相关的干扰素诱导蛋白，作为成骨细胞分化的新调节因子发挥作用。
The differentiation of uncommitted mesenchymal cells into osteoblasts is a fundamental molecular event governing both embryonic development and bone repair. The bone morphogenetic proteins (BMPs) are important regulators of this process; they function by binding to cell surface receptors and signaling by means of Smad proteins. Core binding factor alpha-1 (Cbfa1), a member of the runt family of transcription factors, is an essential transcriptional regulator of osteoblast differentiation and bone formation, and this process is positively or negatively regulated by a variety of coactivators and corepressors. We report that p204, an interferon-inducible protein that was previously shown to inhibit cell proliferation and promote the differentiation of myoblasts to myotubes, is a novel regulator in the course of osteogenesis. p204 is expressed in embryonic osteoblasts and hypertrophic chondrocytes in the growth plate as well as in the calvaria osteoblasts of neonatal mice. Its level is increased in the course of the BMP-2-triggered osteoblast differentiation of pluripotent C2C12 cells. This increase is probably due to the activation of the gene encoding 204 (Ifi2O4) by Smad transcription factor, including Smad1, -4, and -5. Overexpression of p204 enhances the BMP-2-induced osteoblast differentiation in vitro, as revealed by elevated alkaline phosphatase activity and osteocalcin production. p204 acts as a cofactor of Cbfa1: 1) high levels of p204 augment, whereas the lowering of p204 level decreases, the Cbfa1-dependent transcription, and 2) p204 associates with Cbfa1 both in vitro and in vivo. Two nonoverlapping segments in p204 bind to Cbfa1, and the N-terminal 88-amino acid segment of Cbfa1 is required for binding to p204. p204, which is the first interferon-inducible protein found to associate with Cbfa1, functions as a novel regulator of osteoblast differentiation.