Identification of oncogenes by proviral tagging in mouse cancer models II: Analysis of a potentially lymphomagenic locus, Sint2

MH Rasmussen, Graduate student

As an obligate part of their lifecycle the slow-transforming retroviruses integrate randomly into the genome of their host. Enhancer/promoter elements of the inserted provirus may in this manner disturb the expression of host genes neighboring the provirus. Disturbance of proto-oncogenes can confer a selective growth advantage to the infected cell leading to clonal expansion. Using the proviruses as molecular tags, such proto-oncogenes can be identified by reverse genetics. In our model, we make use of the two closely related lymphomagenic murine retroviral strains, SL3-3 and Akv, and derivatives hereof, in a set-up involving a vast number of retrovirally induced tumors. Analyses of these tumors have revealed a 250 kb-region, Sint2 (SL3-3 integration site 2), in which, as of now, we have found integration in 16 independent retrovirally induced tumors, indicating a strong correlation between aberrant expression from genes in this region and development of lymphomas. The integrations cluster around three genes, Fos, Jundp2 and Batf, all encoding transcriptional regulators belonging to the leucine zipper class (bZIP). In mammals, Fos is one major component of the AP-1 complex that repeatedly has been found pivotal in cell differentiation, survival and death. Jundp2, a relatively new member of the bZIP proteins, has been found to repress AP-1 and has consequently been suggested to exert a p53-dependent antiapoptotic effect (Piu et al., Mol Cell Biol. 21(9): 3012-24, 2001). Finally, the product of Batf has been proposed to act as a dominant-negative factor upon AP-1 in the developing hematopoietic system (Williams et al., Eur. J. Immunol. 31: 1620-7, 2001). In order to depict how inappropriate expression of these genes might link with lymphomagenesis we are examining gene expression as well as lineage origins and differentiation stage of the lymphomas. Results from the experiments will be presented.

KEY WORDS: insertional mutagenesis, gene expression, transcriptional regulators.

For more information, contact mhr@mbio.aau.dk

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Viral Oncogenesis.

http://www.cancerprev.org/Journal/Issues/26/101/996/4349