Identification of a MicroRNA that Activates Gene Expression by Repressing Nonsense-Mediated RNA Decay

Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77033, USA.
Molecular cell (Impact Factor: 14.02). 05/2011; 42(4):500-10. DOI: 10.1016/j.molcel.2011.04.018
Source: PubMed


Nonsense-mediated decay (NMD) degrades both normal and aberrant transcripts harboring stop codons in particular contexts. Mutations that perturb NMD cause neurological disorders in humans, suggesting that NMD has roles in the brain. Here, we identify a brain-specific microRNA-miR-128-that represses NMD and thereby controls batteries of transcripts in neural cells. miR-128 represses NMD by targeting the RNA helicase UPF1 and the exon-junction complex core component MLN51. The ability of miR-128 to regulate NMD is a conserved response occurring in frogs, chickens, and mammals. miR-128 levels are dramatically increased in differentiating neuronal cells and during brain development, leading to repressed NMD and upregulation of mRNAs normally targeted for decay by NMD; overrepresented are those encoding proteins controlling neuron development and function. Together, these results suggest the existence of a conserved RNA circuit linking the microRNA and NMD pathways that induces cell type-specific transcripts during development.

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Available from: Jozef Gecz
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    • "Apart from its anti-cancer activity, miR-128 is of particular interest to neuroscientists as it is a brain-enriched miRNA which is highly expressed in the cortex and cerebellum, with distinct patterns of expression in developing brains and maturing cortical neurons (Krichevsky et al., 2003; Kim et al., 2004; Smirnova et al., 2005). Overexpression of miR-128 promotes neuronal differentiation in P19 cells and in primary embryonic neural stem cells through the suppression of non-sense-mediated decay (Bruno et al., 2011; Karam and Wilkinson, 2012). "
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    ABSTRACT: MiRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally. Over the past decade, misregulated miRNA pathways have been associated with various diseases such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. In this article, we aim to discuss the role played by miR-128 in neuropsychiatric disorders, and highlight potential target genes from an in silico analysis of predicted miR-128 targets. We also discuss the differences of target gene determination based on a bioinformatics or empirical approach. Using data from TargetScan and published reports, we narrowed the miR-128 target gene list to those that are known to be associated with neuropsychiatric disorders, and found that these genes can be classified into 29 gene clusters and are mostly enriched in cancer and MAPK signaling pathways. We also highlight some recent studies on several of the miR-128 targets which should be investigated further as potential candidate genes for therapeutic interventions.
    Full-text · Article · Nov 2015 · Frontiers in Cellular Neuroscience
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    • "NMD can be prevented by placing cytoplasmic poly(A) binding protein (PABP) in proximity to the termination codon, suggesting that the increased distance between the translation termination event and cytoplasmic PABP that results from termination at a PTC contributes to NMD (Amrani et al. 2004; Eberle et al. 2008; Ivanov et al. 2008; Silva et al. 2008; Singh et al. 2008; Fatscher et al. 2014). The propensity of long 3 ′ UTRs to induce NMD is also supported by global studies showing enrichment of mRNAs containing long 3 ′ UTRs among endogenous NMD substrates (Mendell et al. 2004; Bruno et al. 2011; Yepiskoposyan et al. 2011; Hurt et al. 2013). Surprisingly, more than one-third of human endogenous mRNAs have 3 ′ UTRs longer than 1000 nt (Pesole et al. 2000), despite artificial 3 ′ UTRs as short as ≈800 nt long triggering NMD (Eberle et al. 2008; Singh et al. 2008; Rebbapragada and Lykke-Andersen 2009; Hogg and Goff 2010; Yepiskoposyan et al. 2011). "
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    ABSTRACT: The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3 ′ UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion. Here, we analyzed a set of human long 3 ′ UTR mRNAs and found that many are indeed resistant to NMD. By dissecting the 3 ′ UTR of one such mRNA, TRAM1 mRNA, we identified a cis element located within the first 200 nt that inhibits NMD when positioned in downstream proximity of the translation termination codon and is sufficient for repressing NMD of a heterologous reporter mRNA. Investigation of other NMD-evading long 3 ′ UTR mRNAs revealed a subset that, similar to TRAM1 mRNA, contains NMD-inhibiting cis elements in the first 200 nt. A smaller subset of long 3 ′ UTR mRNAs evades NMD by a different mechanism that appears to be independent of a termination-proximal cis element. Our study suggests that different mechanisms have evolved to ensure NMD evasion of human mRNAs with long 3 ′ UTRs.
    Full-text · Article · May 2015 · RNA
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    • "As a kind of intronic miRNA, miR-128 is encoded by two distinct genes – miR-128-1 and miR-128-2 – which are embedded in the introns of the R3HDM1 and RCS genes, located on human chromosomes 2q21.3 and 3p22.3, respectively.24 Both miR-128-1 and miR-128-2 are processed to generate the same mature miRNAs with identical sequences – miR-128 – the aberrant expression of which has been observed in many kinds of malignant tumors, including acute lymphoblastic leukemia, acute myeloid leukemia, glioma, osteosarcoma, breast cancer, lung cancer, gastric cancer, pancreatic cancer, colon cancer, prostate cancer, and ovarian cancer.14–21 "
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    ABSTRACT: Objective Abnormal expression of micro-ribonucleic acid (miRNA [miR])-128 has been observed in various human cancer types, and its validated target genes are implicated in cancer-related cellular processes, such as cell proliferation, differentiation, and apoptosis. Especially, it has been demonstrated that miR-128 may play an important role in the proliferation of human osteosarcoma cells in vitro by directly inhibiting PTEN, which functions as a tumor suppressor in this malignancy. In the current study, we investigated the involvement of miR-128 and its target gene PTEN in tumor progression and prognosis in patients with primary osteosarcoma. Materials and methods Expression levels of miR-128 and PTEN messenger RNA in osteosarcoma and noncancerous bone tissues obtained from 100 patients with primary osteosarcoma were detected by quantitative real-time polymerase chain reaction. Results Expression levels of miR-128 and PTEN messenger RNA in osteosarcoma tissues were significantly higher and lower, respectively, than those in noncancerous bone tissues (both P<0.001). In addition, high miR-128 expression and low PTEN expression, alone (miR-128-high or PTEN-low) or combined (miR-128-high/PTEN-low), were all dramatically associated with poor response to chemotherapy and positive metastasis. More importantly, the associations of miR-128-high/PTEN-low expression with these clinicopathological parameters were more significant than miR-128-high or PTEN-low alone. Finally, miR-128 expression, PTEN expression, miR-128/PTEN expression, the response to chemotherapy and the metastatic status were all identified as independent prognostic factors for overall survival and disease-free survival. Conclusion These findings indicate for the first time that the deregulation of miR-128 and its target gene PTEN may be involved in the aggressive progression of human osteosarcoma. Notably, the upregulation of miR-128 cooperating with the downregulation of PTEN may confer an unfavorable prognosis in patients with this malignancy.
    Full-text · Article · Sep 2014 · OncoTargets and Therapy
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