UTRdb and UTRsite: a collection of sequences and regulatory motifs of the untranslated regions of eukaryotic mRNAs

Mignone, Flavio; Grillo, Giorgio; Licciulli, Flavio; Iacono, Michele; Liuni, Sabino; Kersey, Paul J.; Duarte, Jorge; Saccone, Cecilia; Pesole, Graziano

doi:10.1093/nar/gki021

Cited by 145 publications

(121 citation statements)

References 18 publications

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“…cnr.it/UTR/). 32 pmiRGLO vector (Promega, Madison, WI, USA) was used for reporter assay according to manufacturer' instructions. Putative miR-885-5p target sites in the CDK2 and MCM5 3 0 -UTRs were cloned into pmiRGLO vector downstream of the firefly luciferase gene in pmiRGLO vector to create reporter plasmids.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival

et al. 2011

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Several microRNA (miRNA) loci are found within genomic regions frequently deleted in primary neuroblastoma, including miR-885-5p at 3p25.3. In this study, we demonstrate that miR-885-5p is downregulated on loss of 3p25.3 region in neuroblastoma. Experimentally enforced miR-885-5p expression in neuroblastoma cell lines inhibits proliferation triggering cell cycle arrest, senescence and/or apoptosis. miR-885-5p leads to the accumulation of p53 protein and activates the p53 pathway, resulting in upregulation of p53 targets. Enforced miR-885-5p expression consistently leads to downregulation of cyclin-dependent kinase (CDK2) and mini-chromosome maintenance protein (MCM5). Both genes are targeted by miR-885-5p via predicted binding sites within the 3 0 -untranslated regions (UTRs) of CDK2 and MCM5. Transcript profiling after miR-885-5p introduction in neuroblastoma cells reveals alterations in expression of multiple genes, including several p53 target genes and a number of factors involved in p53 pathway activity. Taken together, these data provide evidence that miR-885-5p has a tumor suppressive role in neuroblastoma interfering with cell cycle progression and cell survival. Cell Death and Differentiation (2011) 18, 974-984; doi:10.1038/cdd.2010.164; published online 14 January 2011MicroRNAs (miRNAs) are non-coding short (18-24 nt) RNAs, controlling gene expression post trancriptionally, via inhibiting translation or triggering degradation of multiple target mRNAs. They are vitally important regulators of proliferation, differentiation and apoptosis. Upregulated and downregulated miRNAs have been found in different malignancies, implicating miRNAs as oncogenes or tumor suppressors. 1 The increasing body of evidence for miRNA involvement in tumorigenesis has prompted the search in cancer-associated genomic regions for miRNA loci. 2 In a deletion region at 13q14, miR-15 and miR-16, are downregulated in B-cell chronic lymphocytic leukemia. Both miR-15 and miR-16 negatively regulate BCL2 and positively regulate apoptosis, which could explain their frequent inactivation in leukemia. 3 Later, miR-34a at 1p36 emerged as a tumor suppressor gene (TSG). Several independent studies demonstrated anti-proliferative and pro-apoptotic potential of miR-34a. 4,5 The potential for involvement of as yet unreported miRNAs in cancer pathogenesis is great.Neural crest-derived neuroblastoma, one of the most common solid tumors in children, is frequently characterized as an 'enigmatic neoplasm'. Neuroblastoma has the highest rate of spontaneous regression of all human malignancies, however, B40% of neuroblastomas rapidly progress despite multimodal treatment regimes. 6,7 TP53 mutations are rare in neuroblastoma, which very often retain functional p53, suggesting that inhibitors of the p53 pathway or loss of p53 pathway positive regulators may be involved in neutralizing p53 activity. 8,9 Neuroblastomas with poor outcome are subdivided into at least two biologically distinct groups, either with or without amplification of the MYCN oncogene....

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Section: Discussionmentioning

confidence: 99%

MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival

et al. 2011

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“…We predicted 38 structures in 39 UTRs, a density twofold higher than the genomic average, whereas fewer than 10 such examples are currently known 70 . A considerable fraction of these lies in regulatory genes (14 out of 38; P 5 10 24 ), including several transcriptional regulators (for example, cas, spen and Alh), the tyrosine phosphatase PTP-ER and the translation initiation factor eIF3-S8.…”

Section: Rna Genes and Structuresmentioning

confidence: 92%

Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures

Stark

Lin

Kheradpour³

et al. 2007

Nature

574

566

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Sequencing of multiple related species followed by comparative genomics analysis constitutes a powerful approach for the systematic understanding of any genome. Here, we use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional element shows characteristic patterns of change, or 'evolutionary signatures', dictated by its precise selective constraints. Such signatures enable recognition of new protein-coding genes and exons, spurious and incorrect gene annotations, and numerous unusual gene structures, including abundant stop-codon readthrough. Similarly, we predict non-protein-coding RNA genes and structures, and new microRNA (miRNA) genes. We provide evidence of miRNA processing and functionality from both hairpin arms and both DNA strands. We identify several classes of pre-and post-transcriptional regulatory motifs, and predict individual motif instances with high confidence. We also study how discovery power scales with the divergence and number of species compared, and we provide general guidelines for comparative studies.The sequencing of the human genome and the genomes of dozens of other metazoan species has intensified the need for systematic methods to extract biological information directly from DNA sequence. Comparative genomics has emerged as a powerful methodology for this endeavour 1,2 . Comparison of few (two-four) closely related genomes has proven successful for the discovery of protein-coding genes 3-5 , RNA genes 6,7 , miRNA genes 8-11 and catalogues of regulatory elements 3,4,12-14 . The resolution and discovery power of these studies should increase with the number of genomes [15][16][17][18][19][20] , in principle enabling the systematic discovery of all conserved functional elements.The fruitfly Drosophila melanogaster is an ideal system for developing and evaluating comparative genomics methodologies. Over the past century, Drosophila has been a pioneering model in which many of the basic principles governing animal development and population biology were established 21 . In the past decade, the genome sequence of D. melanogaster provided one of the first systematic views *These authors contributed equally to this work. {Lists of participants and affiliations appear at the end of the paper.

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“…Many transcripts are cleaved and polyadenylated at alternative sites that may depend on cellular contexts (1)(2)(3)(4)(5). The 3Ј UTRs of transcripts frequently contain motifs that regulate their stability and ribosomal translation (6) and their translocation to the cytoplasm. Additionally, these 3Ј UTRs of transcripts may contain miRNA targets and short hairpin loops of regulatory significance.…”

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confidence: 99%

Identification of gene 3′ ends by automated EST cluster analysis

Muro

Herrington

Janmohamed

et al. 2008

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

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The properties and biology of mRNA transcripts can be affected profoundly by the choice of alternative polyadenylation sites, making definition of the 3 ends of transcripts essential for understanding their regulation. Here we show that 22-52% of sequences in commonly used human and murine ''full-length'' transcript databases may not currently end at bona fide polyadenylation sites. To identify probable transcript termini over the entire murine and human genomes, we analyzed the EST databases for positional clustering of EST ends. The analysis yielded 58,282 murine-and 86,410 human-candidate polyadenylation sites, of which 75% mapped to 23,091 known murine transcripts and 22,891 known human transcripts. The murine dataset correctly predicted 97% of the 3 ends in a manually curated and experimentally supported benchmark transcript set. Of currently known genes, 15% had no associated prediction and 25% had only a single predicted termination site. The remaining genes had an average of 3-4 alternative polyadenylation sites predicted for each murine or human transcript, respectively. The results are made available in the form of tables and an interactive web site that can be mined for rapid assessment of the validity of 3 ends in existing collections, enumeration of potential alternative 3 polyadenylation sites of known transcripts, direct retrieval of terminal sequences for design of probes, and detection of polyadenylation sites not currently mapped to known genes.3Ј UTR ͉ gene prediction ͉ alternative polyadenylation ͉ transcriptome ͉ transcript probe design

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UTRdb and UTRsite: a collection of sequences and regulatory motifs of the untranslated regions of eukaryotic mRNAs

Cited by 145 publications

References 18 publications

MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival

MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival

Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures

Identification of gene 3′ ends by automated EST cluster analysis

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