Hudson Barry I, Carter Angela M, Harja Evis, Kalea Anastasia Z, Arriero Maria, Yang Hojin, Grant Peter J, Schmidt Ann Marie
Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., PS 17-401, New York, New York 10032, USA.
FASEB J. 2008 May;22(5):1572-80. doi: 10.1096/fj.07-9909com. Epub 2007 Dec 18.
The receptor for advanced glycation end-products (RAGE) is a single-transmembrane, multiligand receptor of the immunoglobulin superfamily. RAGE up-regulation is implicated in numerous pathological states including vascular disease, diabetes, cancer, and neurodegeneration. The understanding of the regulation of RAGE is important in both disease pathogenesis and normal homeostasis. Here, we demonstrate the characterization and identification of human RAGE splice variants by analysis of RAGE cDNA from tissue and cells. We identified a vast range of splice forms that lead to changes in the protein coding region of RAGE, which we have classified according to the Human Gene Nomenclature Committee (HGNC). These resulted in protein changes in the ligand-binding domain of RAGE or the removal of the transmembrane domain and cytosolic tail. Analysis of splice variants for premature termination codons reveals approximately 50% of identified variants are targeted to the nonsense-mediated mRNA decay pathway. Expression analysis revealed the RAGE_v1 variant to be the primary secreted soluble isoform of RAGE. Taken together, identification of functional splice variants of RAGE underscores the biological diversity of the RAGE gene and will aid in the understanding of the gene in the normal and pathological state.
晚期糖基化终末产物受体（RAGE）是免疫球蛋白超家族的单跨膜、多配体受体。RAGE的上调与包括血管疾病、糖尿病、癌症和神经退行性变在内的多种病理状态有关。了解RAGE的调控在疾病发病机制和正常稳态中都很重要。在这里，我们通过分析来自组织和细胞的RAGE cDNA，展示了人类RAGE剪接变体的特征和鉴定。我们鉴定出了大量导致RAGE蛋白质编码区发生变化的剪接形式，并根据人类基因命名委员会（HGNC）进行了分类。这些变化导致了RAGE配体结合域的蛋白质改变，或跨膜结构域和胞质尾的缺失。对剪接变体中过早终止密码子的分析表明，约50%的已鉴定变体靶向无义介导的mRNA降解途径。表达分析显示RAGE_v1变体是RAGE主要的分泌型可溶性异构体。综上所述，RAGE功能性剪接变体的鉴定突出了RAGE基因的生物学多样性，并将有助于理解该基因在正常和病理状态下的情况。
