期刊
JOURNAL OF BIOCHEMISTRY
卷 147, 期 5, 页码 651-659出版社
OXFORD UNIV PRESS
DOI: 10.1093/jb/mvp207
关键词
alternative splicing; endogenous secretory RAGE (esRAGE); G-stretch; heterogenous nuclear ribonucleoprotein (hnRNP) H; receptor for advanced glycation endproducts (RAGE)
资金
- Japan Society for the Promotion of Sciences [18590260, 19390085, 20590290, 21590304]
- High-Technology Center of Kanazawa Medical University [H2009-10]
- Grants-in-Aid for Scientific Research [21590304, 18590260, 19390085, 20590290] Funding Source: KAKEN
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.
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