TY - JOUR
T1 - Functional Identification of Tumor-Suppressor Genes through an In Vivo RNA Interference Screen in a Mouse Lymphoma Model
AU - Bric, Anka
AU - Miething, Cornelius
AU - Bialucha, Carl Uli
AU - Scuoppo, Claudio
AU - Zender, Lars
AU - Krasnitz, Alexander
AU - Xuan, Zhenyu
AU - Zuber, Johannes
AU - Wigler, Michael
AU - Hicks, James
AU - McCombie, Richard W.
AU - Hemann, Michael T.
AU - Hannon, Gregory J.
AU - Powers, Scott
AU - Lowe, Scott W.
N1 - Funding Information:
We thank B. Ma, K. Diggins-Lehet, J. Simon, M. Yang, E. Earl, and L. Bianco for excellent technical assistance and E. Hernando and L. Chiriboga for immunohistochemistry. We also thank R. Dickins and M. Spector for critical reading of the manuscript, and members of the Lowe laboratory for advice and helpful discussions. This work was supported by postdoctoral fellowships from the NCI (A.B.), the Terri Brodeur Breast Cancer Foundation (C.U.B.), the Deutsche Forschungsgemeinschaft (DFG Mi 1210/1-1, C.C.M.), and a clinical fellowship from Alan and Edith Seligson (L.Z. and J.Z.), as well as research support from the Don Monti Memorial Research Foundation and grants from the National Cancer Institute (CA105388 and CA13106; S.W.L. and G.H.). G.H. and S.W.L. are Howard Hughes Medical Institute Investigators.
PY - 2009/10/6
Y1 - 2009/10/6
N2 - Short hairpin RNAs (shRNAs) capable of stably suppressing gene function by RNA interference (RNAi) can mimic tumor-suppressor-gene loss in mice. By selecting for shRNAs capable of accelerating lymphomagenesis in a well-characterized mouse lymphoma model, we identified over ten candidate tumor suppressors, including Sfrp1, Numb, Mek1, and Angiopoietin 2. Several components of the DNA damage response machinery were also identified, including Rad17, which acts as a haploinsufficient tumor suppressor that responds to oncogenic stress and whose loss is associated with poor prognosis in human patients. Our results emphasize the utility of in vivo RNAi screens, identify and validate a diverse set of tumor suppressors, and have therapeutic implications.
AB - Short hairpin RNAs (shRNAs) capable of stably suppressing gene function by RNA interference (RNAi) can mimic tumor-suppressor-gene loss in mice. By selecting for shRNAs capable of accelerating lymphomagenesis in a well-characterized mouse lymphoma model, we identified over ten candidate tumor suppressors, including Sfrp1, Numb, Mek1, and Angiopoietin 2. Several components of the DNA damage response machinery were also identified, including Rad17, which acts as a haploinsufficient tumor suppressor that responds to oncogenic stress and whose loss is associated with poor prognosis in human patients. Our results emphasize the utility of in vivo RNAi screens, identify and validate a diverse set of tumor suppressors, and have therapeutic implications.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=70349454058&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349454058&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2009.08.015
DO - 10.1016/j.ccr.2009.08.015
M3 - Article
C2 - 19800577
AN - SCOPUS:70349454058
SN - 1535-6108
VL - 16
SP - 324
EP - 335
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -