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Kawasaki H, Taira K. (2003) Hes1 is a target of microRNA-23 during retinoic-acid-induced neuronal differentiation of NT2 cells. Nature 423:838-42.
MicroRNAs (miRNAs) are 21-23 bp RNA molecules that are processed from larger 70-90 bp stem-looped precursors. To date, over 150 miRNAs have been identified in such diverse organisms as worms, fruit flies, humans, and plants (1). The function of most miRNAs is not known. A few miRNAs, however, have been shown to play roles in developmental timing (in worms) and cell proliferation (in fruit flies) by inhibiting the expression of downstream genes (2). Two mechanisms of gene suppression by miRNAs have so far been identified. In one, miRNAs bind to partially complementary regions in the 3' untranslated region (3'UTR) of target transcripts to suppress translation. In the other, the miRNAs bind to perfectly complementary target mRNAs and degrade them via the RNAi pathway.
In the 19 June 2003 issue of Nature, Kawasaki and Taira report on a novel function for a human miRNA. The authors show that miRNA-23 is involved in the differentiation of a human neuronal cell line--a function that is carried out via translational suppression of the Hes1 gene (3). These findings are significant because a function for a human miRNA is identified for the first time.
A Link Between miRNA-23 and Hes1
In order to identify miRNA-23 target genes, Kawasaki and Taira searched the NCBI DNA database for genes with exact matches to human miRNA-23. In their search the best match was found near the termination codon of Hes1 (77% homology)--a basic helix-loop-helix transcriptional repressor that is part of the Notch signaling pathway.
To determine whether the Hes1 mRNA is actually a target for miRNA-23, the authors used NT2 cells as a model system. NT2 cells are embryonic carcinoma cells that differentiate into neuronal cells upon retinoic acid treatment. The authors hypothesized that this differentiation might be dependent on suppression of Hes1 expression by miRNA-23, since it was known that Hes1 up-regulation suppresses neuronal differentiation (4). To confirm their hypothesis, the authors first determined that the levels of HES1 protein (but not Hes1 mRNA) decrease after NT2 cells are treated with retinoic acid. More importantly, they determined that this decrease is accompanied by an increase in miRNA-23 levels. These results suggested that the increase in miRNA-23 levels was causing the reduction in HES1 protein levels in differentiating NT2 cells.
