Identification of oncogenes collaborating with p27Kip1 loss by insertional mutagenesis and high-throughput insertion site analysis.

Publication Type:

Journal Article


Proceedings of the National Academy of Sciences of the United States of America, Volume 99, Issue 17, p.11293-8 (2002)


Animals, Base Sequence, Cell Cycle Proteins, Cloning, Molecular, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, DNA Primers, DNA, Neoplasm, Gene Deletion, Genes, Tumor Suppressor, Lymphoma, MICE, Mice, Knockout, Molecular Sequence Data, Multigene Family, Mutagenesis, Insertional, Oncogenes, Polymerase Chain Reaction, Proto-Oncogenes, Tumor Suppressor Proteins, X Chromosome


The p27(Kip1) protein is a cyclin-dependent kinase inhibitor that blocks cell division in response to antimitogenic cues. p27 expression is reduced in many human cancers, and p27 functions as a tumor suppressor that exhibits haploinsufficiency in mice. Despite the well characterized role of p27 as a cyclin-dependent kinase inhibitor, its mechanism of tumor suppression is unknown. We used Moloney murine leukemia virus to induce lymphomas in p27+/+ and p27-/- mice and observed that lymphomagenesis was accelerated in the p27-/- animals. To identify candidate oncogenes that collaborate with p27 loss, we used a high-throughput strategy to sequence 277 viral insertion sites derived from two distinct sets of p27-/- lymphomas and determined their chromosomal location by comparison with the Celera and public (Ensembl) mouse genome databases. This analysis identified a remarkable number of putative protooncogenes in these lymphomas, which included loci that were novel as well as those that were overrepresented in p27-/- tumors. We found that Myc activations occurred more frequently in p27-/- lymphomas than in p27+/+ tumors. We also characterized insertions within two novel loci: (i) the Jun dimerization protein 2 gene (Jundp2), and (ii) an X-linked locus termed Xpcl1. Each of the loci that we found to be frequently involved in p27-/- lymphomas represents a candidate oncogene collaborating with p27 loss. This study illustrates the power of high-throughput insertion site analysis in cancer gene discovery.