c-Myc-regulated microRNAs modulate E2F1 expression

KA O'Donnell, EA Wentzel, KI Zeller, CV Dang… - nature, 2005 - nature.com
KA O'Donnell, EA Wentzel, KI Zeller, CV Dang, JT Mendell
nature, 2005nature.com
Abstract MicroRNAs (miRNAs) are 21–23 nucleotide RNA molecules that regulate the
stability or translational efficiency of target messenger RNAs. miRNAs have diverse
functions, including the regulation of cellular differentiation, proliferation and apoptosis.
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 …
Abstract
MicroRNAs (miRNAs) are 21–23 nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis. 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. Dysregulated expression or function of c-Myc is one of the most common abnormalities in human malignancy. 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,,. 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.
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