Franceschi Renny T, Xiao Guozhi
Department of Periodontics, School of Dentistry, Ann Arbor, Michigan 48109-1078, USA.
J Cell Biochem. 2003 Feb 15;88(3):446-54. doi: 10.1002/jcb.10369.
The Cbfa1/Runx2 is an important transcription factor necessary for osteoblast differentiation and bone formation. However, the signaling pathways regulating Runx2 activity are just beginning to be understood. Inconsistencies between Runx2 mRNA or protein levels and its transcriptional activity suggests that posttranslational modification and/or protein-protein interactions may regulate this factor. Runx2 can be phosphorylated and activated by the mitogen-activated protein kinase (MAPK) pathway. This pathway can be stimulated by a variety of signals including those initiated by extracellular matrix (ECM), osteogenic growth factors like bone morphogenic proteins (BMPs) and fibroblast growth factor-2 (FGF-2), mechanical loading and hormones such as parathyroid hormone (PTH). Protein kinase A (PKA) may also phosphorylate/activate Runx2 under certain conditions. In addition, Runx2 activity is enhanced by protein-protein interactions as are seen with PTH-induced Runx2/AP-1 and BMP-mediated Runx2/Smads interactions. Mechanisms for interaction with Runx2 are complex including binding of distinct components such as AP-1 factors and Smads proteins to separate DNA regions in target gene promoters and direct physical interactions between Runx2 and AP-1/Smad factors. Post-translational modifications such as phosphorylation may influence interactions between Runx2 and other nuclear factors. These findings suggest that Runx2 plays a central role in coordinating multiple signals involved in osteoblast differentiation.
Cbfa1/Runx2是成骨细胞分化和骨形成所必需的一种重要转录因子。然而,调节Runx2活性的信号通路才刚刚开始被了解。Runx2 mRNA或蛋白水平与其转录活性之间的不一致表明,翻译后修饰和/或蛋白质-蛋白质相互作用可能调节该因子。Runx2可被丝裂原活化蛋白激酶(MAPK)通路磷酸化并激活。该通路可被多种信号刺激,包括由细胞外基质(ECM)引发的信号、成骨生长因子如骨形态发生蛋白(BMPs)和成纤维细胞生长因子-2(FGF-2)、机械负荷以及甲状旁腺激素(PTH)等激素。蛋白激酶A(PKA)在某些条件下也可能磷酸化/激活Runx2。此外,如PTH诱导的Runx2/AP-1和BMP介导的Runx2/Smads相互作用所示,蛋白质-蛋白质相互作用可增强Runx2活性。与Runx2相互作用的机制很复杂,包括不同成分如AP-1因子和Smads蛋白与靶基因启动子中不同DNA区域的结合以及Runx2与AP-1/Smad因子之间的直接物理相互作用。翻译后修饰如磷酸化可能影响Runx2与其他核因子之间的相互作用。这些发现表明,Runx2在协调参与成骨细胞分化的多种信号中起核心作用。