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

  

Authors:	Hemann, M. T.; Fridman, J. S.; Zilfou, J. T.; Hernando, E.; Paddison, P. J.; Cordon-Cardo, C.; Hannon, G. J.; Lowe, S. W.
Article Title:	An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo
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 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 Eμ-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 Eμ-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.
Keywords:	immunohistochemistry; controlled study; unclassified drug; gene mutation; gene sequence; promoter region; sequence analysis; nonhuman; lymph nodes; polymerase chain reaction; ki 67 antigen; animal cell; mouse; phenotype; mammalia; animals; mice; allele; animal tissue; gene; gene targeting; apoptosis; gene expression; animal experiment; animal model; gene locus; alleles; gene function; rna interference; hematopoietic stem cell transplantation; protein p53; mice, inbred c57bl; carcinogenesis; transgenic mouse; animalia; mus musculus; mice, transgenic; rna; gene expression regulation; oncogene; tumor suppressor gene; disease severity; genes, myc; hyperplasia; gene repression; lymphoma; irradiation; reporter gene; hematopoietic stem cell; heterozygosity loss; kaplan meier method; rna processing; short hairpin rna; oncogene myc; genes, p53; expression vector; lymphoid hyperplasia; rna analysis; mitosis index; colony formation; vectors; lymphogenesis; dna content; lymph node hyperplasia; priority journal; article; gene p53; gene trp53; dromaius novaehollandiae
Journal Title:	Nature Genetics
Volume:	33
Issue:	3
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2003-03-01
Start Page:	396
End Page:	400
Language:	English
DOI:	10.1038/ng1091
PUBMED:	12567186
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-0037370309&partnerID=40&md5=9ba923422c40c109775c3c8d52182596
Notes:	Export Date: 12 September 2014 -- Source: Scopus

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