let-7 regulates Dicer expression and constitutes a negative feedback loop

Tokumaru, Shogo; Suzuki, Motoshi; Yamada, Hideki; Nagino, Masato; Takahashi, Takashi

doi:10.1093/carcin/bgn187

Cited by 204 publications

(187 citation statements)

References 27 publications

Supporting

Mentioning

174

Contrasting

Unclassified

Order By: Relevance

“…S1 A and B). Hmga2 and Dicer are validated targets of let-7 (22,23). Let-7 binds to imperfectly complementary sequences in the respective mRNAs, leading to translational repression and mRNA destabilization (22)(23)(24).…”

Section: Resultsmentioning

confidence: 99%

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Mueller

Zhou

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

View full text Add to dashboard Cite

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extra-cellular micro-RNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage.Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/ let-7 regulatory axis also may operate during embryo implantation and development.

show abstract

Section: Resultsmentioning

confidence: 99%

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Mueller

Zhou

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

View full text Add to dashboard Cite

show abstract

“…3A) and performs the last processing step of miRNA maturation before the miRNA is loaded into the RNA-induced silencing complex (RISC). Dicer was recently found to be posttranscriptionally down-regulated by let-7, thus raising the possibility of a let-7-mediated negative-feedback loop (23,30,31).…”

Section: Resultsmentioning

confidence: 99%

A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence

Forman

Legesse‐Miller

Coller

2008

Proc. Natl. Acad. Sci. U.S.A.

540

398

View full text Add to dashboard Cite

Recognition sites for microRNAs (miRNAs) have been reported to be located in the 3 untranslated regions of transcripts. In a computational screen for highly conserved motifs within coding regions, we found an excess of sequences conserved at the nucleotide level within coding regions in the human genome, the highest scoring of which are enriched for miRNA target sequences. To validate our results, we experimentally demonstrated that the let-7 miRNA directly targets the miRNA-processing enzyme Dicer within its coding sequence, thus establishing a mechanism for a miRNA/Dicer autoregulatory negative feedback loop. We also found computational evidence to suggest that miRNA target sites in coding regions and 3 UTRs may differ in mechanism. This work demonstrates that miRNAs can directly target transcripts within their coding region in animals, and it suggests that a complete search for the regulatory targets of miRNAs should be expanded to include genes with recognition sites within their coding regions. As more genomes are sequenced, the methodological approach that we used for identifying motifs with high sequence conservation will be increasingly valuable for detecting functional sequence motifs within coding regions.computational biology ͉ posttranscriptional regulation ͉ comparative genomics ͉ multiple-sequence alignment ͉ evolutionary conservation M icroRNAs (miRNAs) are endogenously encoded, singlestranded regulatory RNAs that bind to and inhibit the translation of transcripts with complementary sequence (1). Computational evidence suggests that miRNAs regulate at least 20% of human genes and have been implicated in the regulation of a wide range of biological systems (2). In plants, miRNA targets can be predicted with relatively high confidence because of the extensive base pairing between plant miRNAs and their target mRNAs (1). In animals, in contrast, miRNAs typically bind to their targets with significantly less complementarity, and the short target sequences are, therefore, difficult to identify on the basis of sequence alone. As a result, most computational approaches to predict miRNA-target interactions rely on conservation of target sites (3-6).Although early studies reported some evidence for the targeting of miRNAs to sites within protein coding regions (4, 6), subsequent research has reported that there is minimal functionality for sites in ORFs or 5Ј UTRs (7). A focus on miRNAs present within 3Ј UTRs is supported by evidence suggesting that the G-cap/poly(A) tail interface (which connects the two ends of eukaryotic mRNAs during translation) is important for miRNA function (8) and that miRNAs tend to be more effective when localized at the end of the 3Ј UTR rather than the middle (7, 9). Indeed, the protein translation machinery might be expected to displace an miRNA complex present within a gene's coding sequence. However, exogenously added siRNAs that target coding sequences, including siRNAs with imperfect base pairing, are effective at silencing (10). More recent reports have also shown that, c...

show abstract

“…In the current study with primary GBM tissues, Dicer was expressed at varying levels, and it would be intriguing to know whether Dicer expression in GBM correlates with prognosis of patients. Interestingly, miR let-7, whose reduced expression was associated with shorter patient survival (4), inhibits Dicer expression by directly targeting the 3Ј UTR of Dicer (21). Therefore, let-7 serves as a prototypic ''tumor-suppressor-miR,'' functioning as a key microRNA in a novel regulatory loop limiting Dicer expression.…”

Section: Discussionmentioning

confidence: 99%