microRNA - August 2013
MicroRNAs (miRNAs) were discovered in the early 1990s in Caenorhabditiselegans and about a decade later their expression in mammals was reported. The literature on miRNA function has since grown exponentially and miRNAs have been implicated as gene regulators in all cellular pathways. Subsequently, miRNAs were found to be mis-regulated in many different diseases including almost all forms of cancer. Today, miRNAs are viewed as fundamental gene regulators embedded into large regulatory networks. Imbalance within such networks leads to cellular malfunctions and to the development of diseases.
miRNAs derive from specific genes, miRNA gene clusters containing more than one miRNA gene or intronic sequences. They are transcribed as primary miRNA transcripts (pri-miRNAs), which are processed by the RNase III enzyme Drosha to stem-loop-structured miRNA precursors (pre-miRNAs). Pre-miRNAs are transported to the cytoplasm, where Dicer, another RNase III enzyme, cleaves off the loop of the pre-miRNA and generates a double-stranded RNA of 18-23 nucleotides. This short-lived intermediate is unwound and one strand is incorporated into the RNA-induced silencing complex (RISC). The other strand, (often referred to as miRNA*), is typically degraded from the cell. In rare cases, however, both strands can give rise to functional miRNAs. Within RISC, the miRNA interacts with a member of the Argonaute (Ago) protein family. miRNAs function as guides for RISC and identify and bind partially complementary sequences typically located in the 3’ untranslated region (UTR) of target mRNAs. As soon as the RISC complex reaches the mRNA, Ago proteins interact with a member of the Glycine-tryptophan repeat (GW) protein family, which mediates all following downstream silencing events. As a consequence, enzymes that remove the poly(A) tail are recruited to the mRNA. Removed poly(A) tails lead to mRNA decapping and subsequent mRNA decay.
In parallel, miRNAs can also affect translation, without reducing mRNA levels. It is believed that one specific miRNA can regulate multiple mRNAs simultaneously. Estimations range from 10 to more than 100 targets per individual miRNA, suggesting that a large portion of the mRNA population is regulated by miRNAs. In cancer, miRNAs can promote or inhibit cancer progression, depending on the targets they regulate. Many such examples have been reported during the last few years and interfering with such miRNAs might develop into a novel strategy for cancer therapy. This virtual issue comprises a collection of papers recently published in the FEBS Journal on specific roles of miRNAs in different forms of cancer, in stem cell biology, in neuronal function or in adipogenesis. Also included are several publications that identified important mechanistical aspects of miRNA function and two review articles that discuss the fundamental roles of miRNAs in fibrosis and epigenetics.
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