MicroRNAs direct rapid deadenylation of mRNA

Skirball Institute of Biomolecular Medicine and Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2006; 103(11):4034-9. DOI: 10.1073/pnas.0510928103
Source: PubMed

ABSTRACT MicroRNAs (miRNAs) are ubiquitous regulators of eukaryotic gene expression. In addition to repressing translation, miRNAs can down-regulate the concentration of mRNAs that contain elements to which they are imperfectly complementary. Using miR-125b and let-7 as representative miRNAs, we show that in mammalian cells this reduction in message abundance is a consequence of accelerated deadenylation, which leads to rapid mRNA decay. The ability of miRNAs to expedite poly(A) removal does not result from decreased translation; nor does translational repression by miRNAs require a poly(A) tail, a 3' histone stem-loop being an effective substitute. These findings suggest that miRNAs use two distinct posttranscriptional mechanisms to down-regulate gene expression.

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    • "The upstream microRNA regulatory mechanism was also examined. MicroRNAs are part of the long transcribed segments of RNA, and a mature microRNA binds to an RNA-mediated silencing complex that is similar to (or the same as) the complex that is involved in RNA interference, resulting in the downregulation of gene expression in vivo (Lewis et al., 2005; Wu et al., 2006). By screening microRNA spectrum, the expression levels of 32 genes were identified as being significantly different, and 3 genes (miR-34a, miR-122, and miR-146a) were closely associated with XZCBF. "
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    ABSTRACT: Xie-Zhuo-Chu-Bi-Fang (XZCBF) is an empirical formula developed based on the principles of traditional Chinese medicine, for the therapeutic purpose of treating hyperuricemia. XZCBF has been clinically utilized in the Department of Traditional Chinese Medicine at General Hospital of Guangzhou Military Command of PLA for many years and has exhibited favorable efficacy. To evaluate the effects of XZCBF on the expression of uric acid transporter 1 (URAT1) and miR-34a in hyperuricemic mice and to determine, the correlation between the two expression levels. A hyperuricemic animal model was created by administering adenine and allantoxanic acid potassium salt to mice. The blood uric acid levels were measured in these model mice after treatment with XZCBF for 15 days. The potential targets of miR-34a were screened. The expression levels of miR-34a and URAT1 in the renal tissues collected from the model mice were determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis; and their correlation was further established by immunohistochemistry and in situ hybridization. The uric acid levels in the model mice were significantly higher than those in the blank controls (P<0.05). These levels were significantly lower in the three groups receiving different doses of XZCBF (P<0.05), which was, in agreement with the downregulation of URAT1 and the upregulation of miR-34a in each group. The mRNA expression level of URAT1 was positively correlated with the concentration of uric acid but, negatively correlated with the expression level of miR-34a. The ability of XZCBF to facilitate the excretion of uric acid and to lower its level in the model group was mediated by the upregulation of miR-34a and the inhibition of URAT1 mRNA expression, which suggests that XZCBF could be an option for the treatment of hyperuricemia in mice. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Journal of Ethnopharmacology 12/2014; 161. DOI:10.1016/j.jep.2014.12.001 · 3.00 Impact Factor
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    • "MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that generally bind through imperfect base pairing to their target mRNAs and repress gene expression by degrading or suppressing translation of the mRNAs [23] [24] [25] [26]. The human genome expresses >2500 miRNAs (, "
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    ABSTRACT: We previously generated a group I intron-based ribozyme that can reprogram human telomerase reverse transcriptase (hTERT) RNA to stimulate transgene activity in cancer cells expressing the target RNA via an accurate and specific trans-splicing reaction. One of the major concerns of the hTERT RNA targeting anti-cancer approach is the potential side effects to hTERT(+) hematopoietic stem cell-derived blood cells. Thus, here we modified the ribozyme by inserting target sites against microRNA-181a, which is a blood cell-specific microRNA, downstream of its 3' exon. The specificity of transgene induction and anticancer activity in hTERT(+) cancer cells improved significantly with the modified ribozyme, resulting in selective targeting of hTERT(+) cancer cells, but not hematopoietic cells even if they are hTERT-positive. Importantly, the trans-splicing reaction of the microRNA-regulated ribozyme worked equally well in a nude mouse model of hepatocarcinoma-derived intrasplenic carcinomatosis, inducing highly specific expression of a therapeutic transgene and efficiently regressing hTERT-positive liver tumors with minimal liver toxicity when systemically delivered with an adenoviral vector encoding the ribozyme. These results suggest that a combined approach of microRNA regulation with targeted RNA replacement is more useful for effective anti-cancer treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Cancer Letters 11/2014; 356(2). DOI:10.1016/j.canlet.2014.11.006 · 5.62 Impact Factor
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    • "Based on the degree of complementarity between the miRNA to 3=UTR of target mRNAs, the mature miRNA negatively regulates the gene expression by two mechanisms: (i) degradation of mRNA and (ii) inhibition of translation initiation. Degradation of the mRNA occurs based on the perfect complementarity between miRNA with target mRNA (Giraldez et al. 2006; Wu et al. 2006). "
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    ABSTRACT: MicroRNAs (miRNAs) are short endogenous non-coding RNA molecules (~22 nucleotides) that can regulate gene expression at the post-transcription level. Research interest in the role of miRNAs in lung biology is emerging. MicroRNAs have been identified in a range of processes such as development, homeostasis and inflammatory diseases in lung tissues, and are capable of inducing differentiation, morphogenesis and apoptosis. In recent years, several studies have reported that miRNAs are differentially regulated in lung development and lung diseases in response to epigenetic changes, providing new insights for their versatile role in various physiological and pathological processes in the lung. In this review, we discuss the contribution of miRNAs to lung development and diseases and possible future implications in the field of lung biology.
    Biochemistry and Cell Biology 11/2014; 10.1139/bcb-2014-0103(2). DOI:10.1139/bcb-2014-0103 · 2.15 Impact Factor
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