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
|
リソース情報 |
ヒト・動物細胞 |
KGN(RCB1154) |