Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model.
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.
Bric
Anka
A
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Miething
Cornelius
C
Bialucha
Carl Uli
CU
Scuoppo
Claudio
C
Zender
Lars
L
Krasnitz
Alexander
A
Xuan
Zhenyu
Z
Zuber
Johannes
J
Wigler
Michael
M
Hicks
James
J
McCombie
Richard W
RW
Hemann
Michael T
MT
Hannon
Gregory J
GJ
Powers
Scott
S
Lowe
Scott W
SW
D042702:Angiopoietin-2 / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D016158:Genes, p53; D005820:Genetic Testing / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics; D011379:Prognosis; D034622:RNA Interference; D015203:Reproducibility of Results; D013997:Time Factors; D014161:Transduction, Genetic; D000094742:Secreted Frizzled-Related Proteins
D042702:Angiopoietin-2; D018797:Cell Cycle Proteins; D036341:Intercellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; C113575:Rad17 protein, human; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C482127:Map2k1 protein, mouse