c-Myc-regulated microRNAs modulate E2F1 expression

Nature. 2005 Jun 9;435(7043):839-43. doi: 10.1038/nature03677.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Cycle Proteins / biosynthesis*
  • Cell Line
  • Chromatin Immunoprecipitation
  • Chromosomes, Human, Pair 13 / genetics
  • DNA-Binding Proteins / biosynthesis*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Gene Expression Regulation*
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Rats
  • Transcription Factors / biosynthesis*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2f1 protein, rat
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors