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Identification and Characterization of Collaborating Oncogenes in Compound Mutant Mice¹

Division of Molecular Genetics, The Netherlands Cancer Institute and Centre of Biomedical Genetics, 1066 CX, Amsterdam, The Netherlands

² To whom requests for reprints should be addressed, at Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

We have used proviral tagging in tumor-prone transgenic mice to identify collaborating oncogenes and genes contributing to tumor progression. This has yielded a series of oncogenes that could be assigned to different complementation groups in transformation: the myc, Pim, Bmi1, and Frat1 complementation groups. Frat1 is involved in tumor progression and appears to function in the Wnt signaling pathway. Overexpression of Frat1 confers a growth advantage to transplanted tumor cells in vivo and to cells grown in vitro at high density. Frat1 might exert its activity by impairing the kinase activity of Gsk3β which is involved in the degradation of β-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 the proliferative defects caused by defective interleukin signaling supporting a role of Pim1 in cell proliferation. We have applied proviral tagging in compound mutant Eµmyc/Pim1^–/–/Pim2^–/– mice to identify genes that can complement for the loss of Pim1 and Pim2 and, therefore, are able to synergize with c-myc in lymphomagenesis. A number of new as well as known genes have been found by this "complementation tagging." The latter included c-kit, Tp12, and cyclin D2, suggesting that Pim kinases might act upstream of or parallel to these known proto-oncogenes.

¹ Presented at the "General Motors Cancer Research Foundation Twentieth Annual Scientific Conference: Developmental Biology and Cancer," June 9–10, 1998, Bethesda, MD. This work was supported by the Dutch Cancer Society (to B. S., J. J., and H. M.), the Netherlands Organization for the Advancement of Research (to P. K.), and the Leukemia Society of America (to J. A.).

Received 9/18/98. Accepted 2/ 5/99.