Regulation of alternative splicing of the receptor for advanced glycation endproducts (RAGE) through G-rich cis-elements and heterogenous nuclear ribonucleoprotein H.
Regulation of alternative splicing of the receptor for advanced glycation endproducts (RAGE) through G-rich cis-elements and heterogenous nuclear ribonucleoprotein H.
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DOI：
10.1093/jb/mvp207
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发表时间：
2010-05
影响因子：
2.7
通讯作者：
Kazuyo Ohe;Takuo Watanabe;S. Harada;Sei-ichi Munesue;Yasuhiko Yamamoto;H. Yonekura;Hiroshi Yamamoto
中科院分区：
文献类型：
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作者：
Kazuyo Ohe;Takuo Watanabe;S. Harada;Sei-ichi Munesue;Yasuhiko Yamamoto;H. Yonekura;Hiroshi Yamamoto
晚期糖基化终产物受体（Receptor for Advanced Glycation Endproducts，RECEPTOR）是一种细胞表面受体。配体与膜结合蛋白（mesenchymal，mesenchymal）的结合引起参与各种病理过程的细胞反应。以前，我们鉴定了一种新的可溶性形式，内源性分泌型β-内酰胺酶（esophagus），其由内含子9中的选择性5'剪接位点选择产生，导致外显子9（外显子9 B）的延伸。由于Esplatin是一种拮抗性诱饵受体，阐明其可变剪接的调控机制对理解RAGE相关的病理过程具有重要意义。在这里，我们确定了富含G的顺式元件内外显子9 B的调节选择性剪接使用一个cDNAminigene。富含G的顺式元件的突变导致小基因转染的细胞中的esp/mesp比率急剧增加，并且RNA基序与异源核核糖核蛋白（hnRNP）H的结合丧失。另一方面，在外显子9 B中人工引入G-延伸引起了伴随着hnRNP H与RNA基序结合的esp/mesp比率的急剧下降。因此，外显子9 B内的G-片段通过与hnRNP H相互作用调节hnRNP选择性剪接。这一发现为开发治疗RAGE相关疾病的药物提供了分子基础，这些药物可以调节雌二醇/孕酮比值。
Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor. The binding of ligands to membrane-bound RAGE (mRAGE) evokes cellular responses involved in various pathological processes. Previously, we identified a novel soluble form, endogenous secretory RAGE (esRAGE) generated by alternative 5' splice site selection in intron 9 that leads to extension of exon 9 (exon 9B). Because esRAGE works as an antagonistic decoy receptor, the elucidation of regulatory mechanism of the alternative splicing is important to understand RAGE-related pathological processes. Here, we identified G-rich cis-elements within exon 9B for regulation of the alternative splicing using a RAGE minigene. Mutagenesis of the G-rich cis-elements caused a drastic increase in the esRAGE/mRAGE ratio in the minigene-transfected cells and in loss of binding of the RNA motif to heterogenous nuclear ribonucleoprotein (hnRNP) H. On the other hand, the artificial introduction of a G-stretch in exon 9B caused a drastic decrease in the esRAGE/mRAGE ratio accompanied by the binding of hnRNP H to the RNA motif. Thus, the G-stretches within exon 9B regulate RAGE alternative splicing via interaction with hnRNP H. The findings should provide a molecular basis for the development of medicines for RAGE-related disorders that could modulate esRAGE/mRAGE ratio.