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A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli (Apc)-dependent intestinal tumorigenesis

Timothy K. Starr, Patricia M. Scott, Benjamin M. Marsh, Lei Zhao, Bich L. N. Than, Gerard O'Sullivan, Aaron L. Sarver, Adam J. Dupuy, David A. Largaespada, Robert T. Cormier and William F. Dove
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 14 (April 5, 2011), pp. 5765-5770
Stable URL: http://www.jstor.org/stable/41125400
Page Count: 6
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A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli (Apc)-dependent intestinal tumorigenesis
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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 ratelimiting 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 ot Ape (Apc Min ) using Sleeping Beauty (SB) transposon-mediated mutagenesis. Apc Min BS-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 Ape locus as a major target of SB-induced mutagenesis, suggesting that SB insertions provide an efficient route to biallelic Ape 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.

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