論文 - 詳細
| RRC ID | 66867 |
|---|---|
| 著者 | Shin E, Jin H, Suh DS, Luo Y, Ha HJ, Kim TH, Hahn Y, Hyun S, Lee K, Bae J. |
| タイトル | An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2. |
| ジャーナル | EMBO J |
| Abstract |
Recent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) in FOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which causes haploinsufficiency of the tumor-suppressor FOXL2. This miR-1236-mediated selective degradation of the variant FOXL2 mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and a mouse model of AGCT, abundance of the inversely regulated variant FOXL2 with miR-1236 levels is highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conserved FOXL2 CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC. |
| 巻・号 | 39(24) |
| ページ | e104719 |
| 公開日 | 2020-12-15 |
| DOI | 10.15252/embj.2020104719 |
| PMID | 33215742 |
| PMC | PMC7737606 |
| MeSH | Allelic Imbalance Animals Apoptosis Argonaute Proteins / genetics Argonaute Proteins / metabolism Cell Death / physiology DEAD-box RNA Helicases / genetics DEAD-box RNA Helicases / metabolism Forkhead Box Protein L2 / genetics* Forkhead Box Protein L2 / metabolism* Gene Expression Regulation, Neoplastic Gene Knockout Techniques Granulosa Cell Tumor / genetics* Granulosa Cell Tumor / pathology HEK293 Cells Humans Mice Mice, Knockout MicroRNAs / genetics MicroRNAs / metabolism* Mutation* Mutation, Missense Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Open Reading Frames* RNA, Messenger / metabolism Transcriptome |
| IF | 9.889 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | KGN(RCB1154) |