Identification and characterization of collaborating oncogenes in compoundmutant mice

We have used proviral tagging in tumor-prone transgenic mice to identify co llaborating oncogenes and genes contributing to tumor progression. This has yielded a series of oncogenes that could be assigned to different compleme ntation groups in transformation: the myc, Firn, Bmi1, and Frat1 complement ation groups. Frat1 is involved in tumor progression and appears to functio n in the Wnt signaling pathway. Overexpression of Frat1 confers a growth ad vantage to transplanted tumor cells ill vivo and to cells grown ill vitro a t high density. Frat1 might exert its activity by impairing the kinase acti vity of Gsk3 beta, which is involved in the degradation of beta-catenin. Pim genes appear to act in tumor initiation and show strong synergism with myc in lymphomagenesis. Overexpression of Pim1 can also overcome some of th e proliferative defects caused by defective interleukin signaling supportin g a role of Pim1 in cell proliferation. We have applied proviral tagging in compound mutant E mu-myc/Pim1(-/-)/Pim2(-/-) mice to identify genes that c an complement for the loss of Pim1 and Pim2 and, therefore, are able to syn ergize with c-myc in lymphomagenesis, A number of new as well as known gene s have been found by this "complementation tagging."' The latter included c -kit, Tpl2, and cyclin D2, suggesting that Pim kinases might act upstream o f or parallel to these known proto-oncogenes.