miR-19 is a key oncogenic component of mir-17-92
- Virginie Olive1,5,
- Margaux J. Bennett1,5,
- James C. Walker1,
- Cong Ma1,
- Iris Jiang1,
- Carlos Cordon-Cardo2,
- Qi-Jing Li3,
- Scott W. Lowe4,
- Gregory J. Hannon4,7 and
- Lin He1,6
- 1Division of Cellular and Developmental Biology, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94705, USA;
- 2Irving Cancer Research Center, New York, New York 10032, USA;
- 3Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710;
- 4Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
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↵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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Footnotes
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↵6 Corresponding authors.
E-MAIL lhe{at}berkeley.edu; FAX (510) 642-9562.
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↵7 E-MAIL hannon{at}cshl.edu; FAX (516) 367-8874.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1861409.
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Supplemental material is available at http://www.genesdev.org.
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- Received September 8, 2009.
- Accepted October 21, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press