PerspectiveMolecular Biology

The Two Faces of miRNA

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Science  21 Dec 2007:
Vol. 318, Issue 5858, pp. 1877-1878
DOI: 10.1126/science.1152623

MicroRNAs (miRNAs) are 20- to 22-nucleotide RNAs that regulate the function of eukaryotic messenger RNAs (mRNAs) and play important roles in development, cancer, stress responses, and viral infections. miRNAs are well known to inhibit the translation of mRNAs into protein and to promote mRNA degradation. On page 1931 of this issue, Vasudevan et al. (1) show that miRNAs can also increase translation, broadening the effect of these small RNAs on protein expression.

To function, a miRNA associates with an Argonaute protein, of which there are four in mammalian cells (Ago1 to Ago4). Each miRNA-Ago complex interacts with a specific mRNA, typically through pairing of nucleotide bases between the miRNA sequence and complementary sequences in the mRNA's 3′-untranslated region (3′UTR). Such 3′UTRs are important assembly sites for complexes that affect mRNA localization, translation, and degradation. How Ago-miRNA complexes repress translation and/or promote mRNA degradation is not clear but involves the recruitment of additional protein factors, most notably the GW182 protein (2).

Vasudevan et al. build on earlier work showing that the 3′UTR of tumor necrosis factor-α (TNF-α) mRNA stimulates translation when mammalian cells are deprived of serum (which contains nutrients and growth factors), arresting the cell division cycle at a particular phase (G1) (3). This stimulation requires Ago2, raising the heretical idea that miRNAs both enhance and repress translation.

Indeed, Vasudevan et al. now show that when cultured mammalian cells are serum-starved (G1 phase arrest), binding of a specific miRNA (miR369-3) to a reporter mRNA (containing the TNF-α 3′UTR) stimulates translation, whereas no stimulation occurs when miR369-3 is absent. In contrast, miR369-3 represses translation during other cell cycle phases. The well-studied “repressive” let7 miRNA and the artificial miRNA mimic cxcr also enhance mRNA translation during starvation-induced G1 arrest, whereas they repress translation elsewhere in the cell cycle. Thus, multiple miRNAs and associated Ago proteins can enhance or repress translation, depending on the cell cycle state.

Stimulation of translation involves a change in the proteins recruited to mRNA by the miRNA-Ago complex (see the figure). During cell cycle arrest, the RNA binding protein FXR1 is recruited to mRNA by the miRNA-Ago complex and stimulates translation (1, 3). Whether other activator proteins are recruited, or repressive proteins (such as GW182) are lost, during this condition is unknown.

Dual functions of miRNAs.

MicroRNAs (miRNAs) can boost or block the translation of target mRNAs. Physiological conditions affect the recruitment of regulatory proteins, which can alter a miRNA's effect.

The diversity of proteins recruited to mRNAs by miRNAs is further broadened by multiple members of the Ago, GW182, and FXR protein families as well as by the expression levels and posttranslational modifications of Ago-interacting proteins. Moreover, the effect of a miRNA-Ago complex can also be modulated by proteins bound to other sites within the 3′UTR. For example, in response to multiple stresses, increased translation of the CAT-1 mRNA in hepatic cells depends on specific binding sites for miRNA-122 in CAT-1 mRNA, and binding of the protein HuR to the 3′UTR (4).

The roles of miRNAs in multiple stress responses hint that other environmental changes may convert some miRNAs to activating roles (5). Moreover, because many of the Ago-interacting proteins (such as FXR1) also bind RNA, some mRNAs might have sequences that constitutively recruit miRNA-Ago complexes that activate translation.

Differential effects of miRNAs at various cell cycle stages or during cellular stress may explain some confusion in the field, including differences in the extent of repression caused by a given miRNA, and the detection of translationally repressed mRNAs with ribosomes. These differences might be explained if cells are distributed differently across the cell cycle in various experiments.

Small RNAs serving as both activators and repressors of gene expression are perhaps not limited to miRNAs. Specific Piwi-interacting RNAs, thought to repress gene expression, may enhance transcription in the fly Drosophila melanogaster (6). Moreover, when delivered into mammalian cells, some double-stranded RNAs complementary to promoter sequences increase gene expression (7, 8).

The present work by Vasudevan et al. raises many questions. What are the mechanisms by which miRNAs enhance translation? Does miRNA stimulation of translation raise a possible complication, and opportunity, in using miRNAs and small interfering RNAs as therapeutics? Finally, assuming miRNAs generally stimulate translation in cells exiting the cell cycle, what role might miRNAs play in developmental and terminal differentiation processes? In a field replete with activity, this latest twist in function may foreshadow even more faces of these intriguing micromolecules.


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