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PMID: 19800577 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study

Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model.

Cancer cell ·Vol. 16 ·No. 4 ·2009-10-06 ·Pages 324-35

Bric A, Miething C, Bialucha CU, Scuoppo C, Zender L, Krasnitz A, Xuan Z, Zuber J, Wigler M, Hicks J, McCombie RW, Hemann MT, Hannon GJ, Powers S, Lowe SW

Abstract

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.

MeSH Terms
Angiopoietin-2/genetics Animals Cell Cycle Proteins/genetics Cell Line, Tumor Cell Transformation, Neoplastic/genetics,metabolism,pathology DNA Damage Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Genes, myc Genes, p53 Genetic Testing/methods Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells/metabolism Humans Intercellular Signaling Peptides and Proteins/genetics Lymphoma/genetics,metabolism,pathology MAP Kinase Kinase 1/genetics Membrane Proteins/genetics Mice Mice, Inbred C57BL Nerve Tissue Proteins/genetics Prognosis RNA Interference Reproducibility of Results Time Factors Transduction, Genetic
Chemicals
Angiopoietin-2 Cell Cycle Proteins Intercellular Signaling Peptides and Proteins Membrane Proteins Nerve Tissue Proteins Numb protein, mouse Rad17 protein, human Sfrp1 protein, mouse MAP Kinase Kinase 1 Map2k1 protein, mouse
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Bric Anka
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
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
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2009.08.015
Published
2009-10-06
Pages
324-35
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2829755
Subset
IM
Grants
NCI NIH HHS · CA13106 · United States
NCI NIH HHS · U01 CA105388-06 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · U01 CA105388 · United States
NCI NIH HHS · P01 CA013106 · United States
NCI NIH HHS · CA105388 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2009.08.015 PMC Full Text View journal details
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