Kashikar Nilesh D, Reiner Jennifer, Datta Arunima, Datta Pran K
Department of Surgery and Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Cell Signal. 2010 Jan;22(1):138-49. doi: 10.1016/j.cellsig.2009.09.024. Epub 2009 Sep 23.
The stromal tissue, made of extracellular matrix and mesenchymal cells, is vital for the functional design of all complex tissues. Fibroblasts are key components of stromal tissue and play a crucial role during organ development, wound repair, angiogenesis and fibrosis. We have previously reported the identification of a novel WD-domain protein, STRAP(1) that inhibits transforming growth factor-beta (TGF-beta) signaling and enhances tumorigenicity via TGF-beta-dependent and TGF-beta-independent mechanisms. Here, we report, for the first time, that deletion of STRAP from Mouse Embryonic Fibroblasts (MEFs) results in a loss of mesenchymal morphology. These cells lose their spindle shape and exhibit features of an epithelial morphology. Gene expression profiling has confirmed that deletion of STRAP affects expression of sets of genes important for diverse functions including cell-cell adhesion and cell polarization, and upregulates E-cadherin expression leading to the formation of adherens junctions, subsequent localization of beta-catenin to the cell membrane and downregulation of the mesenchymal markers like LEF1 (lymphoid enhancer-binding factor 1). Upregulation of WT1 (Wilms tumor homolog 1) in STRAP null MEFs plays a role in E-cadherin induction. Finally, stable expression of STRAP in these cells results in a loss of WT1 and E-cadherin expressions, and a reversal from epithelial to the mesenchymal morphology. Thus, these results provide a novel TGF-beta-independent function of STRAP and describe a mechanism for the role of STRAP in the maintenance of mesenchymal morphology.
由细胞外基质和间充质细胞组成的基质组织，对于所有复杂组织的功能设计至关重要。成纤维细胞是基质组织的关键组成部分，在器官发育、伤口修复、血管生成和纤维化过程中发挥着至关重要的作用。我们之前报道了一种新型WD结构域蛋白STRAP(1)的鉴定，它通过依赖和不依赖转化生长因子-β (TGF-β)的机制抑制TGF-β信号传导并增强肿瘤发生能力。在此，我们首次报道从小鼠胚胎成纤维细胞(MEFs)中缺失STRAP会导致间充质形态的丧失。这些细胞失去纺锤形，呈现上皮形态特征。基因表达谱分析证实，STRAP的缺失影响了对包括细胞间粘附和细胞极化等多种功能重要的基因集的表达，并上调E-钙粘蛋白的表达，导致粘着连接的形成，随后β-连环蛋白定位到细胞膜，以及下调间充质标记物如LEF1(淋巴样增强因子结合因子1)。STRAP缺失的MEFs中WT1(威尔姆斯瘤同源物1)的上调在E-钙粘蛋白的诱导中起作用。最后，这些细胞中STRAP的稳定表达导致WT1和E-钙粘蛋白表达的丧失，以及从上皮形态向间充质形态的逆转。因此，这些结果提供了STRAP一种新的不依赖TGF-β的功能，并描述了STRAP在维持间充质形态中的作用机制。
