miR-19 is a key oncogenic component of mir-17-92.
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.
Olive
Virginie
V
Division of Cellular and Developmental Biology, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94705, USA.
Bennett
Margaux J
MJ
Walker
James C
JC
Ma
Cong
C
Jiang
Iris
I
Cordon-Cardo
Carlos
C
Li
Qi-Jing
QJ
Lowe
Scott W
SW
Hannon
Gregory J
GJ
He
Lin
L
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
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