Takeuchi Tamotsu, Adachi Yoshihiro, Ohtsuki Yuji
Department of Pathology, Kochi Medical School, Nankoku, Kochi, Japan 783-8505.
Am J Pathol. 2005 Jun;166(6):1817-26. doi: 10.1016/S0002-9440(10)62491-1.
Recent research has indicated that ligand-dependent activation of the Notch receptor in stromal cells plays a crucial role in the tumorigenesis of multiple myeloma. Ubiquitination of intracellular regions of Notch receptor and its ligands is important for Notch signal transduction. In vitro autoubiquitination analysis using recombinant proteins identified skeletrophin as a novel RING finger-dependent ubiquitin ligase. Skeletrophin bound the intracellular regions of the Notch ligand Jagged-2, but not to those of Delta-1, -3, -4, or Jagged-1. Skeletrophin, but not its RING-mutated form, ubiquitinized the intracellular region of Jagged-2. In malignant plasma cells from 23 of 40 multiple myeloma specimens, strong skeletrophin expression was observed, especially from patients with osteolytic bone lesions. Cytoplasmic localization, which may indicate Jagged-2 internalization, was found in many skeletrophin-positive myeloma cells. In contrast, skeletrophin was only weakly expressed in a few nonneoplasmic plasma cells in chronically inflamed tissues. Interestingly, exogenous expression of skeletrophin, but not the RING-mutated form, in Jagged-2-positive P3U1 myeloma cells induced Hes-1 (Hairy and Enhancer of Split homolog-1) gene expression in Notch receptor-positive bone marrow stromal cells through direct cell-cell contact. Thus, skeletrophin is a novel ubiquitin ligase that targets the intracellular region of Jagged-2 and is aberrantly overexpressed in multiple myeloma cells, possibly activating Hes-1 on stromal cells through ligand-dependent Notch signaling.
最近的研究表明，基质细胞中Notch受体的配体依赖性激活在多发性骨髓瘤的肿瘤发生中起关键作用。Notch受体及其配体的细胞内区域的泛素化对于Notch信号转导很重要。使用重组蛋白进行的体外自泛素化分析确定骨骼营养蛋白是一种新型的依赖RING结构域的泛素连接酶。骨骼营养蛋白与Notch配体Jagged-2的细胞内区域结合，但不与Delta-1、-3、-4或Jagged-1的细胞内区域结合。骨骼营养蛋白而非其RING结构域突变形式可使Jagged-2的细胞内区域泛素化。在40例多发性骨髓瘤标本中的23例的恶性浆细胞中，观察到骨骼营养蛋白的强表达，尤其是来自有溶骨性骨病变患者的标本。在许多骨骼营养蛋白阳性的骨髓瘤细胞中发现了可能表明Jagged-2内化的细胞质定位。相比之下，骨骼营养蛋白在慢性炎症组织中的少数非肿瘤性浆细胞中仅微弱表达。有趣的是，在Jagged-2阳性的P3U1骨髓瘤细胞中外源表达骨骼营养蛋白而非其RING结构域突变形式，通过直接细胞间接触在Notch受体阳性的骨髓基质细胞中诱导Hes-1（毛状和分裂增强子同源物1）基因表达。因此，骨骼营养蛋白是一种新型泛素连接酶，靶向Jagged-2的细胞内区域，并且在多发性骨髓瘤细胞中异常过表达，可能通过配体依赖性Notch信号传导激活基质细胞上的Hes-1。
