Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse.
Retroviruses, acting as somatic cell insertional mutagens, have been widely used to identify cancer genes in the haematopoietic system and mammary gland. An insertional mutagen for use in other mouse somatic cells would facilitate the identification of genes involved in tumour formation in a wider variety of tissues. Here we report the ability of the Sleeping Beauty transposon to act as a somatic insertional mutagen to identify genes involved in solid tumour formation. A Sleeping Beauty transposon, engineered to elicit loss-of-function or gain-of-function mutations, transposed in all somatic tissues tested and accelerated tumour formation in mice predisposed to cancer. Cloning transposon insertion sites from these tumours revealed the presence of common integration sites, at known and candidate cancer genes, similar to those observed in retroviral mutagenesis screens. Sleeping Beauty is a new tool for unbiased, forward genetic screens for cancer genes in vivo.
Collier
Lara S
LS
Department of Genetics, Cell Biology and Development, The Arnold and Mabel Beckman Center for Transposon Research, The Cancer Center, The University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, USA.
Carlson
Corey M
CM
Ravimohan
Shruthi
S
Dupuy
Adam J
AJ
Largaespada
David A
DA
D000818:Animals; D004251:DNA Transposable Elements / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000235:genetics*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics
D004251:DNA Transposable Elements; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf