Journal article
A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli (Apc)-dependent intestinal tumorigenesis
Proceedings of the National Academy of Sciences - PNAS, Vol.108(14), pp.5765-5770
04/05/2011
DOI: 10.1073/pnas.1018012108
PMCID: PMC3078351
PMID: 21436051
Abstract
It is proposed that a progressive series of mutations and epigenetic events leads to human colorectal cancer (CRC) and metastasis. Furthermore, data from resequencing of the coding regions of human CRC suggests that a relatively large number of mutations occur in individual human CRC, most at low frequency. The functional role of these low-frequency mutations in CRC, and specifically how they may cooperate with high-frequency mutations, is not well understood. One of the most common rate-limiting mutations in human CRC occurs in the adenomatous polyposis coli (
APC
) gene. To identify mutations that cooperate with mutant
APC
, we performed a forward genetic screen in mice carrying a mutant allele of
Apc
(
Apc
Min
) using Sleeping Beauty (
SB
) transposon-mediated mutagenesis.
Apc
Min
SB
-mutagenized mice developed three times as many polyps as mice with the
Apc
Min
allele alone. Analysis of transposon common insertion sites (CIS) identified the
Apc
locus as a major target of
SB
-induced mutagenesis, suggesting that
SB
insertions provide an efficient route to biallelic
Apc
inactivation. We also identified an additional 32 CIS genes/loci that may represent modifiers of the
Apc
Min
phenotype. Five CIS genes tested for their role in proliferation caused a significant change in cell viability when message levels were reduced in human CRC cells. These findings demonstrate the utility of using transposon mutagenesis to identify low-frequency and cooperating cancer genes; this approach will aid in the development of combinatorial therapies targeting this deadly disease.
Details
- Title: Subtitle
- A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli (Apc)-dependent intestinal tumorigenesis
- Creators
- Timothy K Starr - Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer CenterPatricia M Scott - , Duluth, MN 55812Benjamin M Marsh - , Duluth, MN 55812Lei Zhao - , Duluth, MN 55812Bich L. N Than - , Duluth, MN 55812M. Gerard O'Sullivan - Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer CenterAaron L Sarver - Department of Biostatistics and Informatics, Masonic Cancer CenterAdam J Dupuy - Department of Anatomy and Cell BiologyDavid A Largaespada - Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer CenterRobert T Cormier - , Duluth, MN 55812
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.108(14), pp.5765-5770
- DOI
- 10.1073/pnas.1018012108
- PMID
- 21436051
- PMCID
- PMC3078351
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 04/05/2011
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984025372102771
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