miR-19 is a key oncogenic component of mir-17-92

  1. Virginie Olive1,5,
  2. Margaux J. Bennett1,5,
  3. James C. Walker1,
  4. Cong Ma1,
  5. Iris Jiang1,
  6. Carlos Cordon-Cardo2,
  7. Qi-Jing Li3,
  8. Scott W. Lowe4,
  9. Gregory J. Hannon4,7 and
  10. Lin He1,6
  1. 1Division of Cellular and Developmental Biology, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94705, USA;
  2. 2Irving Cancer Research Center, New York, New York 10032, USA;
  3. 3Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710;
  4. 4Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
    1. 5 These authors contributed equally to this work.

    Abstract

    Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Eμ-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt–mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis.

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