title: miR-19 is a key oncogenic component of mir-17-92.
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 Emu-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.
authors.affiliation: Division of Cellular and Developmental Biology, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94705, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Olive
authors.forename: Margaux J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: James C
authors.initials: JC
authors.lastname: Walker
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.forename: Iris
authors.initials: I
authors.lastname: Jiang
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Hannon
authors.forename: Lin
authors.initials: L
authors.lastname: He
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D041681:NIH 3T3 Cells; D051058:Oncogene Protein v-akt / Q000378:metabolism; D009857:Oncogenes / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
chemical_list: D035683:MicroRNAs; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase