Competition and collaboration between RNA‐binding proteins and microRNAs

Advanced Review

J. J. David Ho, Philip A. Marsden

Published Online: Oct 07 2013

DOI: 10.1002/wrna.1197

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Posttranscriptional regulation of mRNA species represents a major regulatory checkpoint in the control of gene expression. Historically, RNA‐binding proteins (RBPs) have been regarded as the primary regulators of mRNA stability and translation. More recently, however, microRNAs have emerged as a class of potent and pervasive posttranscriptional rheostats that similarly affect mRNA stability and translation. The observation that both microRNAs and RBPs regulate mRNA stability and translation has initiated a newer area of research that involves the examination of dynamic interactions between these two important classes of posttranscriptional regulators, the myriad of factors that influence these biological interactions, and ultimately, their effects on target mRNAs. Specifically, microRNAs and RBPs can act synergistically to effect mRNA destabilization and translational inhibition. They can also engage in competition with each other and exert opposing effects on target mRNAs. To date, several key studies have provided critical details regarding the mechanisms and principles of interaction between these molecules. Additionally, these findings raise important questions regarding the regulation of these interactions, including the roles of posttranslational modification, subcellular localization, target inhibition versus activation, and changes in expression levels of these regulatory factors, especially under stimulus‐ and cell‐specific conditions. Indeed, further experimentation is warranted to address these key issues that pertain to the collaboration and competition between microRNAs and RBPs. Significantly, the elucidation of these important details bears critical implications for disease management, especially for those diseases in which these cellular factors are dysregulated. WIREs RNA 2014, 5:69–86. doi: 10.1002/wrna.1197 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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External stimuli that down‐regulate endothelial nitric oxide synthase (eNOS) mRNA stability. Several pathophysiological stimuli have been shown to result in decreased eNOS mRNA stability, including cytokines such as tumor necrosis factor (TNF)‐α, hypoxia, entry into cell cycle, and oxidized low density lipoprotein (LDL). Decreased mRNA stability contributes significantly to overall decreased eNOS expression and activity under these conditions, thereby highlighting the biological importance of the posttranscriptional regulation of eNOS.

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Functional importance of Dicer in the adaptive cellular response to hypoxia. Dicer and an important number of Dicer‐dependent microRNAs are down‐regulated under chronic hypoxic conditions via multiple mechanisms. This functions as an important adaptive cellular response to chronic hypoxia that serves to maintain the cellular hypoxic response through hypoxia‐inducible factor‐α (HIF‐α)‐ and microRNA‐dependent mechanisms. Specifically, a significant proportion of down‐regulated microRNAs are predicted regulators of hypoxia‐inducible genes, including the critical hypoxia‐inducible factor‐α (HIF‐α) subunits, GLUT1, BNIP3L, VEGFA, as well as VEGFR1 and VEGFR2. In particular, the hypoxic down‐regulation of the Dicer‐dependent microRNA miR‐185 contributes to the hypoxic induction of HIF‐2α.

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Active stabilization of endothelial nitric oxide synthase (eNOS) mRNA by hnRNP E1. (Top panel) hnRNP E1 interacts with key pyrimidine (C/CU)‐rich elements in the eNOS 3′‐UTR, and protects eNOS mRNAs from microRNA‐mediated inhibition in normal endothelial cells. (Bottom panel) Under chronic hypoxic conditions, hnRNP E1 exhibits increased serine phosphorylation, particularly at serine 43, as well as increased nuclear localization, both in an AKT‐dependent manner. These events effectively inhibit the interaction between hnRNP E1 and eNOS mRNAs, thus rendering eNOS susceptible to the inhibitory, hypoxia‐inducible natural cis‐antisense transcript, sONE. MiR‐765, although abundant in normoxic endothelial cells, is significantly down‐regulated in chronic hypoxia in a Dicer‐dependent manner.

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The canonical microRNA biogenesis pathway. MicroRNAs are initially transcribed in the nucleus as primary microRNA transcripts (pri‐miRNAs), where they are processed by Drosha into precursor microRNAs (pre‐miRNAs). Pre‐miRNAs are then exported into the cytoplasm by Exportin‐5 in a RAN‐GTP‐dependent manner, where they are processed by Dicer into ˜22nt mature microRNAs (miRNAs). MiRNAs are then incorporated into RNA‐induced silencing complexes (RISCs), which are effector complexes that mediate microRNA‐dependent translational inhibition and/or mRNA degradation.

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