International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

TUESDAY OCTOBER 19

9.00am – 9.15am

SOMATIC SLEEPING BEAUTY TRANSPOSITION PROVIDES A POTENTIALLY POTENT CANCER GENE DISCOVERY TOOL

Jenkins NA, Dupuy AJ, Copeland NG

National Cancer Institute, Frederick, United States

Transposon-induced insertional mutagenesis has been a valuable tool for functional genomics in invertebrates and holds great promise for functional genomic studies in mouse.  Sleeping Beauty (SB), a synthetic “cut-and-paste” transposon of the Tc1/mariner class, transposes at low frequencies in mouse ES cells (3.5 X 10-6 transposition events/cell per generation) and higher frequencies in the mouse germ line (1-2 transposition events per animal born), but these frequencies are too low to be useful for most genetic screens.  Sleeping Beauty is a two-part system consisting of the transposon and the transposase enzyme.  When both elements are present in the same cell, the transposase binds to the inverted repeats present at the ends of the transposon facilitating its excision and reintegration at a new site in the host cell genome.  We have generated an enhanced SB mutagenesis system that holds great promise for cancer gene discovery.  Transgenic mice were created that harbor 100-300 tandem copies of a genetically enhanced SB transposon in addition to a line of mice that carry a genetically enhanced transposase at the Rosa26 locus.  Approximately 75% of the mice produced that carry both elements died during development, presumably as a result of somatic transposition-mediated developmental defects.  Mice that were born died between 6 and 16 weeks of age from aggressive hematopoietic malignancies.  Tumors from these mice contained multiple (10-20 or more) SB transpositions and some of these transpositions were located at sites of known cancer genes. Our experiments demonstrate the power of somatic SB transposition for cancer gene discovery.  SB elements can transpose in both dividing as well as in non-dividing cells unlike retroviruses, which integrate into the genome only during cell division.  In principle, therefore, somatic SB transposition could induce tumors in a wide variety of cell types and provide a nearly universal cancer gene discovery tool.

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