Mechanism of translational regulation by miR-2 from sites in the 5¢ untranslated region or the open reading frame. Rna

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
RNA (Impact Factor: 4.62). 10/2010; 16(12):2493-502. DOI: 10.1261/rna.2384610
Source: PubMed

ABSTRACT MicroRNAs (miRs) commonly regulate translation from target mRNA 3' untranslated regions (UTRs). While effective miR-binding sites have also been identified in 5' untranslated regions (UTRs) or open reading frames (ORFs), the mechanism(s) of miR-mediated regulation from these sites has not been defined. Here, we systematically investigate how the position of miR-binding sites influences translational regulation and characterize their mechanistic basis. We show that specific translational regulation is elicited in vitro and in vivo not only from the 3'UTR, but equally effectively from six Drosophila miR-2-binding sites in the 5'UTR or the ORF. In all cases, miR-2 triggers mRNA deadenylation and inhibits translation initiation in a cap-dependent fashion. In contrast, single or dual miR-2-binding sites in the 5'UTR or the ORF yield rather inefficient or no regulation. This work represents the first demonstration that 5'UTR and ORF miR-binding sites can function mechanistically similarly to the intensively investigated 3'UTR sites. Using single or dual binding sites, it also reveals a biological rationale for the high prevalence of miR regulatory sites in the 3'UTR.

Download full-text


Available from: Francesca Moretti, Jan 24, 2014
  • Source
    • "The mechanism by which a miRNA can diminish protein expression is unclear, but several proposals are there from different experimental evidences. miRNAs can interfere with translation process at the stage of initiation (Figure 2) or elongation (Figure 3), or target mRNA may be affected by isolating it from ribosomal machinery [8] [9] [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The production of different types of blood cells including their formation, development, and differentiation is collectively known as haematopoiesis. Blood cells are divided into three lineages erythriod (erythrocytes), lymphoid (B and T cells), and myeloid (granulocytes, megakaryocytes, and macrophages). Haematopoiesis is a complex process regulated by several mechanisms including microRNAs (miRNAs). miRNAs are small RNAs which regulate the expression of a number of genes involved in commitment and differentiation of hematopoietic stem cells. Evidence shows that miRNAs play an important role in haematopoiesis; for example, myeloid and erythroid differentiation is blocked by the overexpression of miR-15a. miR-221, miR-222, and miR-24 inhibit the erythropoiesis, whereas miR-150 plays a role in B and T cell differentiation. miR-146 and miR-10a are downregulated in megakaryopoiesis. Aberrant expression of miRNAs was observed in hematological malignancies including chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myelomas, and B cell lymphomas. In this review we have focused on discussing the role of miRNA in haematopoiesis.
    Advances in Hematology 12/2013; 2013:695754. DOI:10.1155/2013/695754
  • Source
    • "In animals, miRNAs are phylogenetically conserved and primarily inhibit transcript translation by binding in the 3′ untranslated region (UTR) sequences of targeted gene transcripts (Bartel, 2004; Lee et al., 1993; Wightman et al., 1993). However, there is growing evidence that miRNAs also posttranscriptionally regulate gene expression through complementary binding in the 5′ UTRs (Lee et al., 2009; Lytle et al., 2007; Moretti et al., 2010) and coding regions (Tay et al., 2008; Zhou et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Testicular toxicity is an important safety endpoint in drug development and risk assessment, but reliable and translatable biomarkers for predicting injury have eluded researchers. However, this area shows great potential for improvement, with several avenues currently being pursued. This was the topic of a symposium session during the 2013 Society of Toxicology Annual Meeting in San Antonio, TX, entitled (")Translatable Indicators of Testicular Toxicity: Inhibin B, microRNAs, and Sperm Signatures.(") This symposium brought together stakeholders from academia, government, and industry to present the limitations and drawbacks of currently used indicators of injury, and discussed the ongoing efforts in developing more predictive biomarkers of injury. The presentations highlighted the early challenges of using circulating inhibin B and microRNA levels, and sperm mRNA transcript abundance and DNA methylation profiles, as novel biomarkers of testicular toxicity.
    Toxicological Sciences 09/2013; DOI:10.1093/toxsci/kft207 · 4.48 Impact Factor
  • Source
    • "This miRNA mediated regulation is sequence-specific and occurs at post-transcriptional level [He and Hannon, 2004]. Recently, miRNA has been also shown to target 5′ UTR or the open reading frames of targeted mRNA [Moretti et al., 2010]. miRNAs have been found in mitochondria [Bian et al., 2010; Kren et al., 2009], and they can contribute to mitochondrial dysfunction [Li et al., 2011]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria supply energy for physiological function and they participate in the regulation of other cellular events including apoptosis, calcium homeostasis, and production of reactive oxygen species. Thus, mitochondria play a critical role in the cells. However, dysfunction of mitochondria is related to a variety of pathological processes and diseases. MicroRNAs (miRNAs) are a class of small noncoding RNAs about 22 nucleotides long, and they can bind to the 3'-untranslated region (3'-UTR) of mRNAs, thereby inhibiting mRNA translation or promoting mRNA degradation. We summarize the molecular regulation of mitochondrial metabolism, structure, and function by miRNAs. Modulation of miRNAs levels may provide a new therapeutic approach for the treatment of mitochondria-related diseases.
    Journal of Cellular Biochemistry 04/2012; 113(4):1104-10. DOI:10.1002/jcb.24004 · 3.37 Impact Factor
Show more