1. Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model.
- Author
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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, and Lowe SW
- Subjects
- Angiopoietin-2 genetics, Animals, Cell Cycle Proteins genetics, Cell Line, Tumor, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, DNA Damage, Genes, myc, Genes, p53, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells metabolism, Humans, Intercellular Signaling Peptides and Proteins 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, Time Factors, Transduction, Genetic, Cell Transformation, Neoplastic genetics, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Genetic Testing methods, Lymphoma genetics, RNA Interference
- 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.
- Published
- 2009
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