An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo

Hemann, M. T., Fridman, J. S., Zilfou, J. T., Hernando, E., Paddison, P. J., Cordon-Cardo, C., Hannon, G. J., Lowe, S. W. (March 2003) An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nature Genetics, 33 (3). pp. 396-400. ISSN 1061-4036

URL: http://www.ncbi.nlm.nih.gov/pubmed/12567186
DOI: 10.1038/ng1091

Abstract

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 disease(1,2). 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 Emu-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 Emu-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.

Item Type: Paper
Uncontrolled Keywords: C ELEGANS c elegans INTERFERENCE interference SUPPRESSION suppression CANCER cancer MOUSE mouse GENES genes DICER dicer
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene silencing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
therapies > stem cells
CSHL Authors:
Communities: CSHL labs > Hannon lab
CSHL labs > Lowe lab
Watson School > Publications
Depositing User: Editor Margaret Fantz
Date: 1 March 2003
Date Deposited: 17 Apr 2012 18:36
Last Modified: 19 Sep 2014 14:42
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26107

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