c-Myc-regulated microRNAs modulate E2F1 expression

MicroRNAs ( miRNAs) are 21 - 23 nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs1. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis(2). Although strict tissue- and developmental-stage-specific expression is critical for appropriate miRNA function, mammalian transcription factors that regulate miRNAs have not yet been identified. The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth and apoptosis(3). Dysregulated expression or function of c-Myc is one of the most common abnormalities in human malignancy(4). Here we show that c-Myc activates expression of a cluster of six miRNAs on human chromosome 13. Chromatin immunoprecipation experiments show that c-Myc binds directly to this locus. The transcription factor E2F1 is an additional target of c-Myc that promotes cell cycle progression(5-7). We find that expression of E2F1 is negatively regulated by two miRNAs in this cluster, miR-17-5p and miR-20a. These findings expand the known classes of transcripts within the c-Myc target gene network, and reveal a mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal.