Nature Genetics
- 33, 396 - 400 (2003)
Published online: 3 February 2003; | doi:10.1038/ng1091
An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivoMichael T. Hemann1, Jordan S. Fridman1, Jack T. Zilfou1, Eva Hernando2, Patrick J. Paddison1, Carlos Cordon-Cardo2, Gregory J. Hannon1 & Scott W. Lowe11
Cold Spring Harbor Laboratory, Watson School of Biological Sciences, Cold Spring Harbor, New York 11724, USA. 2
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Correspondence should be addressed to Gregory J. Hannon hannon@cshl.org or Scott W. Lowe lowe@cshl.org The application of RNA interference (RNAi) to mammalian systems has the potential to revolutionize genetics and produce novel therapies. Here we investigate whether RNAi applied to a well-characterized gene can stably suppress gene expression in hematopoietic stem cells and produce detectable phenotypes in mice. Deletion of the Trp53 tumor suppressor gene greatly accelerates Myc-induced lymphomagenesis, resulting in highly disseminated disease1,
2. To determine whether RNAi suppression of Trp53 could produce a similar phenotype, we introduced several Trp53 short hairpin RNAs (shRNAs) into hematopoietic stem cells derived from E -Myc transgenic mice, and monitored tumor onset and overall pathology in lethally irradiated recipients. Different Trp53 shRNAs produced distinct phenotypes in vivo, ranging from benign lymphoid hyperplasias to highly disseminated lymphomas that paralleled Trp53-/- lymphomagenesis in the E-Myc mouse. In all cases, the severity and type of disease correlated with the extent to which specific shRNAs inhibited p53 activity. Therefore, RNAi can stably suppress gene expression in stem cells and reconstituted organs derived from those cells. In addition, intrinsic differences between individual shRNA expression vectors targeting the same gene can be used to create an 'epi-allelic series' for dissecting gene function in vivo.
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