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Insertional Mutagenesis

Flip'in beautiful

Nature Reviews Cancer volume 9, page 229 (2009)Cite this article

David Largaespada and colleagues have developed a lox–stop–lox (lsl) version of the transposase allele SB11 and knocked this into the ubiquitously expressed mouse Rosa26 locus. SB11 can be activated in any target tissue through the use of a tissue-specific Cre recombinase. Use of this technology in mice that harbour multiple copies of the T2/onc mutagenic transposon enables activation of transposition in a tissue-specific manner.

In their mouse model of hepatocellular carcinoma (HCC), Vincent Keng and colleagues used hepatocyte-specific albumin–Cre (Alb–Cre) to activate SB11 in the liver. They analysed two related mouse models: triple transgenics (Rosa26–lsl–SB11;T2/onc;Alb–Cre) and quadruple transgenics (Rosa26–lsl–SB11;T2/onc;Alb–Cre;Trp53–lsl–R207H) that also expressed a lsl dominant negative Trp53 allele. (p53 is frequently mutated in human HCC.) Lesions in both triple and quadruple transgenics were evident around day 160 after birth, but were larger and more frequent in the quadruple transgenics. HCC in both mouse models was similar to human HCC, including the gender bias: the disease was more frequent in males than females. The authors carried out PCR and pyrosequencing to identify the transposon insertion sites in pre-neoplastic lesions from 3 triple and 65 quadruple transgenic animals. They identified 19 common insertion sites (CIS) that are associated with HCC. The epidermal growth factor receptor ( Egfr ) was the most commonly mutated gene (85% of pre-neoplastic nodules), which makes sense given that the region containing EGFR is amplified in human HCC and mutation of EGFR in a mouse model of liver repopulation resulted in pre-neoplastic cell growth. In addition, 17 of the CIS genes are implicated in human HCC.

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ORIGINAL RESEARCH PAPER

  1. Keng, V. W. et al. A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellullar carcinoma. Nature Biotech. 22 Feb 2009 (doi: 10.1038/nbt.1526)

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  2. Starr, T. K. et al. A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science 26 Feb 2009 (doi: 10.1126/science.1163040)

    Article  CAS  Google Scholar 

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Authors
  1. Nicola McCarthy
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McCarthy, N. Flip'in beautiful. Nat Rev Cancer 9, 229 (2009). https://doi.org/10.1038/nrc2634

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  • DOI: https://doi.org/10.1038/nrc2634

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