A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis
Virginie Olive,
Erich Sabio,
Margaux J Bennett,
Caitlin S De Jong,
Anne Biton,
James C McGann,
Samantha K Greaney,
Nicole M Sodir,
Alicia Y Zhou,
Asha Balakrishnan,
Mona Foth,
Micah A Luftig,
Andrei Goga,
Terence P Speed,
Zhenyu Xuan,
Gerard I Evan,
Ying Wan,
Alex C Minella,
Lin He
Affiliations
Virginie Olive
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Erich Sabio
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Margaux J Bennett
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Caitlin S De Jong
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Anne Biton
Department of Statistics, University of California, Berkeley, Berkeley, United States
James C McGann
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Samantha K Greaney
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Nicole M Sodir
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Alicia Y Zhou
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
Asha Balakrishnan
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
Mona Foth
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Micah A Luftig
Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
Andrei Goga
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
Terence P Speed
Department of Statistics, University of California, Berkeley, Berkeley, United States
Zhenyu Xuan
Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Dallas, United States
Gerard I Evan
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Ying Wan
Department of Medicine, The Third Military Medical University, Chongqing, China
Alex C Minella
Driskill Graduate Program, Department of Medicine, Hematology and Oncology Division, Northwestern University Feinberg School of Medicine, Chicago, United States
Lin He
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
mir-17-92, a potent polycistronic oncomir, encodes six mature miRNAs with complex modes of interactions. In the Eμ-myc Burkitt’s lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. This miR-92 effect is, at least in part, mediated by its direct repression of Fbw7, which promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to aberrant c-Myc increase, imposing a strong coupling between excessive proliferation and p53-dependent apoptosis. Interestingly, miR-92 antagonizes the oncogenic miR-19 miRNAs; and such functional interaction coordinates proliferation and apoptosis during c-Myc-induced oncogenesis. This miR-19:miR-92 antagonism is disrupted in B-lymphoma cells that favor a greater increase of miR-19 over miR-92. Altogether, we suggest a new paradigm whereby the unique gene structure of a polycistronic oncomir confers an intricate balance between oncogene and tumor suppressor crosstalk.
