Individual microRNAs (miRNAs) display distinct mRNA targeting “rules”

Wang, Wang‐Xia; Wilfred, Bernard R.; Xie, Kevin; Jennings, Mary H.; Hu, Yanling; Stromberg, Arnold J.; Nelson, Peter T.

doi:10.4161/rna.7.3.11693

Cited by 51 publications

(45 citation statements)

References 36 publications

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“…Comparison of the potential 3Ј-UTR targeting sequence of Bcl-2 with that of Mcl-1 demonstrates a remarkable homology between these sequences, which includes conservation within the seed sequence. The seed sequence is a key region of complementary necessary for the targeting of miRNAs (Wang et al, 2010b). Our results demonstrated that mutation of the nucleotides complementary to the miR181 seed sequence in the 3Ј-UTR of Mcl-1 ablated the effects of miR181b.…”

Section: Discussionmentioning

confidence: 67%

Lyn Kinase-Dependent Regulation of miR181 and Myeloid Cell Leukemia-1 Expression: Implications for Drug Resistance in Myelogenous Leukemia

Zimmerman¹,

Dollins²,

Crawford³

et al. 2010

Mol Pharmacol

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Imatinib, a BCR-Abl inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). Despite the success of imatinib, multiple mechanisms of resistance remain a problem, including overexpression of Lyn kinase (Lyn) and Bcl-2 family antiapoptotic proteins. Profiling micro-RNA (miRNA) expression in a model of Lyn-mediated imatinibresistant CML (MYL-R) identified approximately 30 miRNAs whose expression differed Ͼ2-fold compared with drugsensitive MYL cells. In particular, the expression of the miR181 family (a-d) was significantly reduced (ϳ11-to 25-fold) in MYL-R cells. Incubation of MYL-R cells with a Lyn inhibitor (dasatinib) or nucleofection with Lyn-targeting short interfering RNA increased miR181b and miR181d expression. A similar Lyn-dependent regulation of miR181b and miR181d was observed in imatinib-resistant K562 CML cells. Sequence analysis of potential targets for miR181 regulation predicted myeloid cell leukemia-1 (Mcl-1), a Bcl-2 family member whose expression is increased in MYL-R cells and drug-resistant leukemias. Inhibition of Lyn or rescue of miR181b expression reduced Mcl-1 expression in the MYL-R cells. To further investigate the mechanism of Mcl-1 repression by miR181, a luciferase reporter construct incorporating the Mcl-1 3Ј-untranslated region was tested. Overexpression of miR181b reduced luciferase activity, whereas these effects were ablated by the mutation of the seed region of the miR181 target site. Finally, stimulation of Lyn expression by 1,25-dihydroxyvitamin D 3 treatment in HL-60 cells, a cell model of acute myelogenous leukemia, decreased miR181b expression and increased Mcl-1 expression. In summary, our results suggest that Lyn-dependent regulation of miR181 is a novel mechanism of regulating Mcl-1 expression and cell survival.

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Section: Discussionmentioning

confidence: 67%

Lyn Kinase-Dependent Regulation of miR181 and Myeloid Cell Leukemia-1 Expression: Implications for Drug Resistance in Myelogenous Leukemia

Zimmerman¹,

Dollins²,

Crawford³

et al. 2010

Mol Pharmacol

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“…Surprisingly, most of the significantly altered genes lack putative miR-181c regulation sites, suggesting that a large number of these genes are possibly regulated by miR-181c in a non-canonical manner. It has recently become evident that miRs can indeed control gene expression in an indirect manner [33,34]. Thus, within our identified gene set miR-181c may control a number of genes in this mode of action.…”

Section: Discussionmentioning

confidence: 74%

MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons

Kos

Loohuis

Meinhardt

et al. 2016

Cell. Mol. Life Sci.

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MicroRNAs (miRs) are non-coding gene transcripts abundantly expressed in both the developing and adult mammalian brain. They act as important modulators of complex gene regulatory networks during neuronal development and plasticity. miR-181c is highly abundant in cerebellar cortex and its expression is increased in autism patients as well as in an animal model of autism. To systematically identify putative targets of miR-181c, we repressed this miR in growing cortical neurons and found over 70 differentially expressed target genes using transcriptome profiling. Pathway analysis showed that the miR-181c-modulated genes converge on signaling cascades relevant to neurite and synapse developmental processes. To experimentally examine the significance of these data, we inhibited miR-181c during rat cortical neuronal maturation in vitro; this loss-of miR-181c function resulted in enhanced neurite sprouting and reduced synaptogenesis. Collectively, our findings suggest that miR-181c is a modulator of gene networks associated with cortical neuronal maturation.

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“…This and other studies suggest that miR-338 has multiple downstream targets with converging roles in neural growth and development. Furthermore, it has also become increasingly clear that miRs can modulate gene expression in an indirect manner [54,55]. This non-canonical gene regulation could be facilitated by directly regulating the expression of transcription factors, RNA binding molecules, components of the nonsense-mediated mRNA decay pathway or modulate the activity of the RNA translation system [56,54,57].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-338 Attenuates Cortical Neuronal Outgrowth by Modulating the Expression of Axon Guidance Genes

et al. 2016

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MicroRNAs (miRs) are small non-coding RNAs that confer robustness to gene networks through post-transcriptional gene regulation. Previously, we identified miR-338 as a modulator of axonal outgrowth in sympathetic neurons. In the current study, we examined the role of miR-338 in the development of cortical neurons and uncovered its downstream mRNA targets. Long-term inhibition of miR-338 during neuronal differentiation resulted in reduced dendritic complexity and altered dendritic spine morphology. Furthermore, monitoring axon outgrowth in cortical cells revealed that miR-338 overexpression decreased, whereas inhibition of miR-338 increased axonal length. To identify gene targets mediating the observed phenotype, we inhibited miR-338 in cortical neurons and performed whole-transcriptome analysis. Pathway analysis revealed that miR-338 modulates a subset of transcripts involved in the axonal guidance machinery by means of direct and indirect gene targeting. Collectively, our results implicate miR-338 as a novel regulator of cortical neuronal maturation by fine-tuning the expression of gene networks governing cortical outgrowth.

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Individual microRNAs (miRNAs) display distinct mRNA targeting “rules”

Cited by 51 publications

References 36 publications

Lyn Kinase-Dependent Regulation of miR181 and Myeloid Cell Leukemia-1 Expression: Implications for Drug Resistance in Myelogenous Leukemia

Lyn Kinase-Dependent Regulation of miR181 and Myeloid Cell Leukemia-1 Expression: Implications for Drug Resistance in Myelogenous Leukemia

MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons

MicroRNA-338 Attenuates Cortical Neuronal Outgrowth by Modulating the Expression of Axon Guidance Genes

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