A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis

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 a...

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Bibliographic Details
Published in:eLife 2013-10, Vol.2, p.e00822-e00822
Main Authors: Olive, Virginie, Sabio, Erich, Bennett, Margaux J, De Jong, Caitlin S, Biton, Anne, McGann, James C, Greaney, Samantha K, Sodir, Nicole M, Zhou, Alicia Y, Balakrishnan, Asha, Foth, Mona, Luftig, Micah A, Goga, Andrei, Speed, Terence P, Xuan, Zhenyu, Evan, Gerard I, Wan, Ying, Minella, Alex C, He, Lin
Format: Article
Language:English
Subjects:
Animals
Annealing
Antagonism
Apoptosis
Apoptosis - genetics
Apoptosis - physiology
Biology
c-Myc
c-Myc protein
Cell cycle
Cells, Cultured
Cloning
Cooperation
Eμ-myc lymphoma
Gene expression
Genes and Chromosomes
Kinases
Lymphocytes B
Lymphoma
Mice
microRNA
MicroRNAs - physiology
Mutation
Myc protein
Oncogenes
p53
p53 Protein
Standard deviation
Target recognition
Tumor suppressor genes
Tumorigenesis
Vertebrates
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Summary: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. DOI:http://dx.doi.org/10.7554/eLife.00822.001.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.00822