TY - JOUR
T1 - A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors
AU - Voorhoeve, P Mathijs
AU - le Sage, Carlos
AU - Schrier, Mariette
AU - Gillis, Ad J M
AU - Stoop, Hans
AU - Nagel, Remco
AU - Liu, Ying-Poi
AU - van Duijse, Josyanne
AU - Drost, Jarno
AU - Griekspoor, Alexander
AU - Zlotorynski, Eitan
AU - Yabuta, Norikazu
AU - De Vita, Gabriella
AU - Nojima, Hiroshi
AU - Looijenga, Leendert H J
AU - Agami, Reuven
N1 - Funding Information:
We thank Martijn Kedde and Hugo Horlings for technical help, Ron Kerkhoven and Mike Heimerikx for support in microarray analysis, Steve de Jong for reagents, Wigard Kloosterman for help in miRNA-in situ protocol, J. Wolter Oosterhuis for supportive work for histology, and Alexandra Pietersen for critical reading of the manuscript. This work was supported by grants from the Dutch Cancer Society to P.M.V., C.S., and R.A. and by the EURYI award to R.A.
PY - 2006/3/24
Y1 - 2006/3/24
N2 - Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumor-suppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.
AB - Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumor-suppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.
KW - Cells, Cultured
KW - Genetic Testing
KW - Humans
KW - Male
KW - MicroRNAs/classification
KW - Neoplasms, Germ Cell and Embryonal/genetics
KW - Oncogenes
KW - Protein Serine-Threonine Kinases/antagonists & inhibitors
KW - Signal Transduction
KW - Testicular Neoplasms/genetics
KW - Tumor Suppressor Proteins/antagonists & inhibitors
UR - https://www.scopus.com/pages/publications/33646056975
U2 - 10.1016/j.cell.2006.02.037
DO - 10.1016/j.cell.2006.02.037
M3 - Article
C2 - 17695719
SN - 0092-8674
VL - 124
SP - 1169
EP - 1181
JO - Cell
JF - Cell
IS - 6
ER -