title: c-Myc-regulated microRNAs modulate E2F1 expression.
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.
authors.affiliation: Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: O'Donnell
authors.forename: Erik A
authors.initials: EA
authors.lastname: Wentzel
authors.forename: Karen I
authors.initials: KI
authors.lastname: Zeller
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493755:E2f1 protein, rat; C000715470:MAS1 protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors