A modified sleeping beauty transposon system that can be used to model a wide variety of human cancers in mice

Adam J Dupuy; Laura M Rogers; Jinsil Kim; Kishore Nannapaneni; Timothy K Starr; Pentao Liu; David A Largaespada; Todd E Scheetz; Nancy A Jenkins; Neal G Copeland

doi:10.1158/0008-5472.CAN-09-1135

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A modified sleeping beauty transposon system that can be used to model a wide variety of human cancers in mice

Journal article

Open access

Peer reviewed

A modified sleeping beauty transposon system that can be used to model a wide variety of human cancers in mice

Adam J Dupuy, Laura M Rogers, Jinsil Kim, Kishore Nannapaneni, Timothy K Starr, Pentao Liu, David A Largaespada, Todd E Scheetz, Nancy A Jenkins and Neal G Copeland

Cancer research (Chicago, Ill.), Vol.69(20), pp.8150-8156

10/15/2009

DOI: 10.1158/0008-5472.CAN-09-1135

PMCID: PMC3700628

PMID: 19808965

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https://doi.org/10.1158/0008-5472.CAN-09-1135View

Published (Version of record) Open Access

Abstract

Recent advances in cancer therapeutics stress the need for a better understanding of the molecular mechanisms driving tumor formation. This can be accomplished by obtaining a more complete description of the genes that contribute to cancer. We previously described an approach using the Sleeping Beauty (SB) transposon system to model hematopoietic malignancies in mice. Here, we describe modifications of the SB system that provide additional flexibility in generating mouse models of cancer. First, we describe a Cre-inducible SBase allele, RosaSBase(LsL), that allows the restriction of transposon mutagenesis to a specific tissue of interest. This allele was used to generate a model of germinal center B-cell lymphoma by activating SBase expression with an Aid-Cre allele. In a second approach, a novel transposon was generated, T2/Onc3, in which the CMV enhancer/chicken beta-actin promoter drives oncogene expression. When combined with ubiquitous SBase expression, the T2/Onc3 transposon produced nearly 200 independent tumors of more than 20 different types in a cohort of 62 mice. Analysis of transposon insertion sites identified novel candidate genes, including Zmiz1 and Rian, involved in squamous cell carcinoma and hepatocellular carcinoma, respectively. These novel alleles provide additional tools for the SB system and provide some insight into how this mutagenesis system can be manipulated to model cancer in mice.

Humans

Male

Green Fluorescent Proteins - genetics

Intracellular Signaling Peptides and Proteins - metabolism

Lymphoma, B-Cell - genetics

RNA, Messenger - metabolism

Immunoenzyme Techniques

Carcinoma, Hepatocellular - genetics

DNA Transposable Elements - genetics

Female

Integrases - metabolism

Liver Neoplasms, Experimental - genetics

Liver Neoplasms, Experimental - pathology

Nuclear Proteins - genetics

Intracellular Signaling Peptides and Proteins - genetics

Disease Models, Animal

Skin Neoplasms - pathology

Green Fluorescent Proteins - metabolism

Mice, Inbred C57BL

RNA, Messenger - genetics

Mice, Transgenic

Nuclear Proteins - metabolism

Mutation - genetics

Reverse Transcriptase Polymerase Chain Reaction

Mice, Inbred C3H

Animals

Skin Neoplasms - genetics

Carcinoma, Hepatocellular - pathology

Lymphoma, B-Cell - pathology

Mice

Mutagenesis, Insertional

Monte Carlo Method

Details

Title: Subtitle: A modified sleeping beauty transposon system that can be used to model a wide variety of human cancers in mice
Creators: Adam J Dupuy - Department of Anatomy and Cell Biology, Center for Bioinformatics, Computational Biology and Biomedical Engineering, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. adam-dupuy@uiowa.edu
Laura M Rogers
Jinsil Kim
Kishore Nannapaneni
Timothy K Starr
Pentao Liu
David A Largaespada
Todd E Scheetz
Nancy A Jenkins
Neal G Copeland
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.69(20), pp.8150-8156
Publisher: United States
DOI: 10.1158/0008-5472.CAN-09-1135
PMID: 19808965
PMCID: PMC3700628
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: R01 CA113636 / NCI NIH HHS
Language: English
Date published: 10/15/2009
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Anatomy and Cell Biology; Pathology; Holden Comprehensive Cancer Center; Ophthalmology and Visual Sciences
Record Identifier: 9983979978102771

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