Takayama Sachiko, Rogatsky Inez, Schwarcz Leslie E, Darimont Beatrice D
Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, OR 97403-1229, USA.
J Biol Chem. 2006 Jun 30;281(26):17856-63. doi: 10.1074/jbc.M602290200. Epub 2006 Apr 27.
The ability of glucocorticoids (GCs) to regulate cell proliferation plays an important role in their therapeutic use. The canonical Wnt pathway, which promotes the proliferation of many cancers and differentiated tissues, is an emerging target for the actions of GCs, albeit existing links between these signaling pathways are indirect. By screening known Wnt target genes for their ability to respond differently to GCs in cells whose proliferation is either positively or negatively regulated by GCs, we identified c-myc, c-jun, and cyclin D1, which encode rate-limiting factors for G(1) progression of the cell cycle. Here we show that in U2OS/GR cells, which are growth-arrested by GCs, the glucocorticoid receptor (GR) represses cyclin D1 via Tcf-beta-catenin, the transcriptional effector of the canonical Wnt pathway. We demonstrate that GR can bind beta-catenin in vitro, suggesting that GC and Wnt signaling pathways are linked directly through their effectors. Down-regulation of beta-catenin by RNA interference impeded the expression of cyclin D1 but not of c-myc or c-jun and had no significant effect on the proliferation of U2OS/GR cells. Although these results revealed that beta-catenin and cyclin D1 are not essential for the regulation of U2OS/GR cell proliferation, considering the importance of the Wnt pathway for proliferation and differentiation of other cells, the repression of Tcf-beta-catenin activity by GR could open new possibilities for tissue-selective GC therapies.
糖皮质激素（GCs）调节细胞增殖的能力在其治疗应用中起着重要作用。经典Wnt信号通路可促进多种癌症和分化组织的增殖，尽管这些信号通路之间现有的联系是间接的，但它正成为GCs作用的一个新靶点。通过筛选已知的Wnt靶基因，观察其在细胞增殖受GCs正向或负向调控的细胞中对GCs的不同反应能力，我们鉴定出了c-myc、c-jun和细胞周期蛋白D1，它们编码细胞周期G1期进程的限速因子。在此我们表明，在被GCs诱导生长停滞的U2OS/GR细胞中，糖皮质激素受体（GR）通过经典Wnt信号通路的转录效应因子Tcf-β-连环蛋白抑制细胞周期蛋白D1。我们证明GR在体外可与β-连环蛋白结合，这表明GC和Wnt信号通路通过它们的效应因子直接相连。通过RNA干扰下调β-连环蛋白可抑制细胞周期蛋白D1的表达，但不影响c-myc或c-jun的表达，且对U2OS/GR细胞的增殖无显著影响。尽管这些结果表明β-连环蛋白和细胞周期蛋白D1对U2OS/GR细胞增殖的调节并非必需，但考虑到Wnt信号通路对其他细胞增殖和分化的重要性，GR对Tcf-β-连环蛋白活性的抑制可能为组织选择性GC治疗开辟新的途径。
