Posttranscriptional Regulation of miRNAs Harboring Conserved Terminal Loops

Michlewski, Gracjan; Guil, Sònia; Semple, Colin A.; Cáceres, Javier F.

doi:10.1016/j.molcel.2008.10.013

Cited by 310 publications

(350 citation statements)

References 40 publications

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“…Lin28 and hnRNP A1 interact with Drosha by binding to the terminal loop region of pri-let-7 and pri-miR-18a, respectively. 30,31 The signal transducers of the transforming growth factor β/bone morphogenetic protein, the Smads, promote the expression of a subset of miRNAs, including miR-21 and miR-199a, by facilitating the cleavage reaction by Drosha. 16,32 In response to DNA damage, p53 interacts with the Drosha processing complex through its association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs, which enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145.…”

Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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Radioresistance is a major obstacle in successful clinical cancer radiotherapy, and the underlying mechanisms are not clear. Here we show that IKKα-mediated miR-196a biogenesis via interaction with Drosha regulates the sensitivity of nasopharyngeal carcinoma (NPC) cells to radiotherapy. Phosphorylation of IKKα at T23 site (p-IKKαT23) promotes the binding of IKKα to Drosha that accelerates the processing of miR-196a primary transcripts, leading to increased expressions of both precursor and mature miR-196a. Dephosphorylation of p-IKKαT23 downregulates miR-196a expression and promotes the resistance of NPC cells to radiation treatment. The miR-196a mimic suppresses while its inhibitor promotes the resistance of NPC to radiation treatment. Importantly, the expression of p-IKKαT23 is positively related to the expression of miR-196a in human NPC tissues, and expression of p-IKKαT23 and miR-196a is inversely correlated with NPC clinical radioresistance. Thus, our studies establish a novel mechanistic link between the inactivation of IKKαT23-Drosha-miR-196a pathway and NPC radioresistance, and de-inactivation of IKKαT23-Drosha-miR-196a pathway would be an efficient way to restore the sensitivity of radioresistant NPC to radiotherapy.

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Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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“…The abundance of the six miRNAs correlate relatively well except for miR-18a, whose processing has been shown to be regulated by binding of hnRNPA1 to its conserved terminal loop. 32,42 In particular, the abundance of miR-18a is strikingly low in naive B cells. A study of miR-17-92 during mouse development also showed that expression of the individual miRNAs of the cluster did not vary entirely in parallel, 34 with miR-18a showing a disproportionate decrease in several postnatal tissues compared with the embryo.…”

Section: Discussionmentioning

confidence: 99%

“…The miRNA whose level correlated least well with the others was miR-18a ( Figure 1A and inset). Processing of this miRNA is known to be regulated by an RNA-binding protein 32 ; variation in efficiency of miR-18a processing among different cell lines is likely to be responsible for the relatively low correlation between miR-18a levels and those of the other members of the cluster. Of the 11 cell lines, the greatest amounts of miR-17-92 expression were seen in JeKo-1 (a mantle cell lymphoma line) and in DHL16 (a DLBCL line of the germinal center B-cell subtype).…”

Section: Expression Of the Mir-17-92 Cluster In B Cellsmentioning

confidence: 99%

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

Rao

Ramachandrareddy

et al. 2011

The American Journal of Pathology

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A cluster of six microRNAs (miRNAs), miR-17-92, is processed from the transcript of C13orf25, a gene amplified in some lymphomas and solid tumors. We find that levels of the miRNAs in the cluster do not vary entirely in parallel with each other or with the primary RNA in B-cell lines or normal cells, suggesting that processing or stability of the miRNAs is differentially regulated. Using luciferase reporter assays, we identified the region required for maximum promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually have only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. MYC is known to regulate C13orf25; surprisingly, mutation of a putative promoter MYCbinding site enhanced promoter activity. We found that the inhibitory MYC family member MXI1 bound to this region. The chromatin structure of a >22.5-kb region encompassing the gene contains peaks of activating histone marks, suggesting the presence of enhancers, and we confirmed that at least two regions have enhancer activity. Because MicroRNAs (miRNAs) are single-stranded RNAs of ϳ22 nucleotides that negatively regulate expression of their target genes posttranscriptionally. 1-4 Various miRNAs are overexpressed or underexpressed in different types of cancer in humans and may function as either tumor suppressors or oncogenes. 5-13 A cluster of six miRNAs (miR-17-92, comprising miR-17, miR18a, miR-20a, miR-19a, miR-19b-1, and miR-92a-1) is processed from the transcript of C13orf25 (also known as MIR17HG or MIRHG1), a gene amplified in some lymphomas and solid tumors 5,14 -17 and overexpressed in a large fraction of lymphomas. 5 Overexpression of miR-17-92 accelerates lymphomagenesis in mouse models. 5,8 The miRNAs in the cluster can target transcripts of genes, such as E2F1, PTEN, and BIM, which are important in cell proliferation and apoptosis. 18 -22 The transcriptional regulation of the miR-17-92 cluster, however, is poorly understood.C13orf25 is activated by MYC and E2F transcription factors, and MYC was first shown to bind to a region containing a conserved CATGTG sequence in the first intron of the gene locus. 8 By chromatin immunoprecipitation (ChIP) in HeLa cells, endogenous E2F1, E2F2, and E2F3 were found to directly bind the promoter of the gene and regulate its transcription. 21 The primary transcript initiates from a consensus initiator sequence downstream of a nonconsensus TATA box. 23 This TATA box is flanked by a TP53 binding site that medi-

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“…Some studies indicate that the hnRNP A1 binds to the loop region of miR-18, contained in the cluster mir17-92, generating a structural rearrangement in the hairpin that promotes Drosha cleavage, favoring the independent and unique processing of miR-18. 96 The loop region of miR-18a is evolutionarily conserved, suggesting that some other well-conserved loop regions can be modulated by this mechanism (Fig. 2A).…”

Section: Drosha Processing and Alterations In Cancermentioning

confidence: 99%