1. Program in Human Genetics and Molecular Biology,
2. The Institute of Genetic Medicine,
3. Departments of Medicine and
4. Pediatrics, and
5. the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Correspondence to: Joshua T. Mendell^1,2,4 Correspondence and requests for materials should be addressed to J.T.M. (Email: jmendell@jhmi.edu).

Abstract

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 apoptosis². 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 apoptosis³. Dysregulated expression or function of c-Myc is one of the most common abnormalities in human malignancy⁴. 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, 6, 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.

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