Subramaniam Malayannan, Cicek Muzaffer, Pitel Kevin S, Bruinsma Elizabeth S, Nelson Holte Molly H, Withers Sarah G, Rajamannan Nalini M, Secreto Frank J, Venuprasad K, Hawse John R
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Division of Cardiology, Most Sacred Heart of Jesus Cardiology and Valvular Institute, Sheboygan, WI 53081, USA.
Nucleic Acids Res. 2017 May 19;45(9):5170-5182. doi: 10.1093/nar/gkx118.
We have previously demonstrated that TGFβ Inducible Early Gene-1 (TIEG1), also known as KLF10, plays important roles in mediating skeletal development and homeostasis in mice. TIEG1 has also been identified in clinical studies as one of a handful of genes whose altered expression levels or allelic variations are associated with decreased bone mass and osteoporosis in humans. Here, we provide evidence for the first time that TIEG1 is involved in regulating the canonical Wnt signaling pathway in bone through multiple mechanisms of action. Decreased Wnt signaling in the absence of TIEG1 expression is shown to be in part due to impaired β-catenin nuclear localization resulting from alterations in the activity of AKT and GSK-3β. We also provide evidence that TIEG1 interacts with, and serves as a transcriptional co-activator for, Lef1 and β-catenin. Changes in Wnt signaling in the setting of altered TIEG1 expression and/or activity may in part explain the observed osteopenic phenotype of TIEG1 KO mice as well as the known links between TIEG1 expression levels/allelic variations and patients with osteoporosis.
我们之前已经证明，转化生长因子β诱导早期基因-1（TIEG1），也称为KLF10，在介导小鼠骨骼发育和体内平衡中发挥重要作用。在临床研究中，TIEG1也被确定为少数几个基因之一，其表达水平改变或等位基因变异与人类骨量减少和骨质疏松症有关。在此，我们首次提供证据表明，TIEG1通过多种作用机制参与调节骨骼中的经典Wnt信号通路。在缺乏TIEG1表达的情况下，Wnt信号降低部分是由于AKT和GSK-3β活性改变导致β-连环蛋白核定位受损。我们还提供证据表明，TIEG1与Lef1和β-连环蛋白相互作用，并作为它们的转录共激活因子。在TIEG1表达和/或活性改变的情况下，Wnt信号的变化可能部分解释了观察到的TIEG1基因敲除小鼠的骨质减少表型，以及TIEG1表达水平/等位基因变异与骨质疏松症患者之间的已知联系。
