The complexity of miRNA-mediated repression

Wilczynska, Ania; Bushell, Martin

doi:10.1038/cdd.2014.112

Cited by 393 publications

(315 citation statements)

References 163 publications

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“…Posttranslational modifications (PTMs) have recently emerged as a potential mechanism for directly regulating miRISC activity (20). To date, a limited number of studies have addressed the functional role of PTMs of miRNA pathway machinery.…”

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confidence: 99%

Casein kinase II promotes target silencing by miRISC through direct phosphorylation of the DEAD-box RNA helicase CGH-1

Alessi

Khivansara

Han

et al. 2015

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

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MicroRNAs (miRNAs) play essential, conserved roles in diverse developmental processes through association with the miRNA-induced silencing complex (miRISC). Whereas fundamental insights into the mechanistic framework of miRNA biogenesis and target gene silencing have been established, posttranslational modifications that affect miRISC function are less well understood. Here we report that the conserved serine/threonine kinase, casein kinase II (CK2), promotes miRISC function in Caenorhabditis elegans. CK2 inactivation results in developmental defects that phenocopy loss of miRISC cofactors and enhances the loss of miRNA function in diverse cellular contexts. Whereas CK2 is dispensable for miRNA biogenesis and the stability of miRISC cofactors, it is required for efficient miRISC target mRNA binding and silencing. Importantly, we identify the conserved DEAD-box RNA helicase, CGH-1/DDX6, as a key CK2 substrate within miRISC and demonstrate phosphorylation of a conserved N-terminal serine is required for CGH-1 function in the miRNA pathway.

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mentioning

confidence: 99%

Casein kinase II promotes target silencing by miRISC through direct phosphorylation of the DEAD-box RNA helicase CGH-1

Alessi

Khivansara

Han

et al. 2015

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

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“…This report corroborates this concept by extending the role of the miR-17 family to early angiogenic events, an important initial step in tumor progression. Because each miR can theoretically bind to and regulate hundreds of targets, one of the most intriguing questions concerns the translational regulation of the target genes (30). In the ROP model, we observed a consistent reduction of all six miR-17 family members and a corresponding increase in Hif1a and Vegfa protein levels within hours after mice pups were returned to room air after 5 d of high O 2 exposure.…”

Section: Low Levels Of Mir-17 Family In the Initial Steps Of The Angimentioning

confidence: 74%

Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch

Nunes

Dias-Neto

Cardó-Vila

et al. 2015

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

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Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3′ UTRs of Hif1a and Vegfa. Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response. In humans, the miR-17 family is composed of six distinct mature miRs located on three chromosomes: miR-17-5p and miR-20a are located on chromosome 13q31.3, miR-20b and miR106a are located on chromosome Xq26.2, and miR-106b and miR-93 are located on chromosome 7q22.1. Members of this family seem to be derived from gene duplication events (9), and despite some divergences in length and nucleotide composition, their seed sequence (AAAGUG) is identical, an attribute suggestive of functional redundancy (10). Although the miR-17-92 cluster has been well-characterized, the regulatory role of the miR-17 family members has not been extensively studied (11,12). Distinct prediction algorithms (13-16) indicate that the miR-17 miR family may target the 3′ UTRs of genes encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Therefore, by simultaneously targeting these two key genes, miR-17 family members could, in theory, be important concerted regulators of angiogenesis. As proof of concept, we tested this hypothesis in the experimental mouse model of retinopathy of prematurity (ROP), where Vegfa seems to be a pivotal factor that modulates the angiogenic switch (17)(18)(19). In this model, the expression of retinal Vegfa mRNA increases sharply 12 h after the animals are returned from 75% oxygen (O 2 ) back to room air (∼21% O 2 ), a process that induces a relative hypoxic condition and leads to retinal neovascularization in the subsequent 9 d (17-19).Here, we show the synchronous down-regulation of all members of the miR-17 family in the critical early steps of neovascularization in the ROP model. We propose an miR regulatory network, in which distinct and partially redundant miR-17 family members simultaneously affect the levels of the Hif1a transcription factor to posttranscriptionally (either directly and/or indirectly) increase the expres...

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“…Shortening of mRNA 3′UTR causes loss of miRNA target sites and post-transcriptional upregulation of critical oncogenes in cancer cells. On the other hand, lengthening of 3′UTRs and increasing the number of potential miRNA binding sites in mRNAs has been observed during mouse embryonic development, indicating that alterations in miRNA regulation can lead to pathological processes [12].…”

Section: Brief Summary Of Mirna Biogenesis and Functionmentioning

confidence: 99%