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 suppre...

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Bibliographic Details
Published in:Cancer cell 2009-10, Vol.16 (4), p.324-335
Main Authors: Bric, Anka, Miething, Cornelius, Bialucha, Carl Uli, Scuoppo, Claudio, Zender, Lars, Krasnitz, Alexander, Xuan, Zhenyu, Zuber, Johannes, Wigler, Michael, Hicks, James, McCombie, Richard W., Hemann, Michael T., Hannon, Gregory J., Powers, Scott, Lowe, Scott W.
Format: Article
Language:English
Subjects:
Angiopoietin-2 - genetics
Animals
Cell Cycle Proteins - genetics
Cell Line, Tumor
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
CELLCYCLE
DNA Damage
Gene Expression Regulation, Neoplastic
Genes, myc
Genes, p53
Genes, Tumor Suppressor
Genetic Testing - methods
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells - metabolism
Humans
Intercellular Signaling Peptides and Proteins - genetics
Lymphoma - genetics
Lymphoma - metabolism
Lymphoma - pathology
MAP Kinase Kinase 1 - genetics
Membrane Proteins - genetics
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins - genetics
Prognosis
Reproducibility of Results
RNA Interference
Time Factors
Transduction, Genetic
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2009.08.015