Identification of oncogenes collaborating with p27 ^Kip1 loss by insertional mutagenesis and high-throughput insertion site analysis

Abstract

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.

JDP2 suppresses adipocyte differentiation by regulating histone acetylation

“…We and others reported that JDP2 is an AP-1 transcriptional repressor 15,[17][18][19][20] with histone-chaperone activity that inhibits histone acetylation by recruiting HDAC3. 24 JDP2 also inhibited the RA-dependent differentiation of embryonic carcinoma F9 cells.…”

“…12,13 Jun dimerization protein 2 (JDP2) is a DNA-binding protein that forms homodimers or heterodimers with c-Jun, ATF2 and C/EBPg. [14][15][16] JDP2 can function not only as a transcriptional repressor but also as a coactivator in various types of cell, 15,[17][18][19][20] and it is involved in a variety of biological phenomena such as proliferation and differentiation of cells and apoptosis. 14,15,17,18,[20][21][22] For example, forced expression of JDP2 represses the retinoic acid-mediated (RA-mediated) transcription of the c-jun gene and the differentiation of F9 cells in response to RA.…”

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

“…In contrast to other studies using the MMLV or in the AKXD or BXH2 inbred mouse lines to accelerate pre-T and pre-B lymphomas or myeloid leukemias (Li et al, 1999;Hwang et al, 2002;Kim et al, 2003;Erkeland et al, 2004;Iwasaki et al, 2004;Shin et al, 2004), this approach exploited the preferential tropism of the mAIDS virus for mature B lymphocytes and successfully accelerated cancer progression in IgHm-HOX11 Tg mice. The relatively low number of integrations observed (B1.9 per tumor) is consistent with reports that the Du5H mAIDS virus yields fewer (between 2 and 4) integration events when compared to MMLV (between 6 and 10) or with other models of recombinant inbred mouse strains characterized by laterally transmitted retroviruses (Huang et al, 1995).…”

“…Retroviral-derived DNA sequences that integrate adjacent to cellular oncogenes or within coding regions of tumor suppressors, can result in altered host gene expression contributing, ultimately, to clonal expansion of the infected cell. While the proviral tagging approach has resulted in the discovery of many genes involved in lymphoid and myeloid leukemias (Li et al, 1999;Hwang et al, 2002;Kim et al, 2003;Erkeland et al, 2004;Iwasaki et al, 2004;Shin et al, 2004), less work has been conducted on mature B-cell lymphomas.…”

MicroRNAs and genomic instability

“…11 reside the genes Dph1, Cis8 and Pps. Integration into a region spanning 4 kb to 23 kb 5′ of Dph1, which would be predicted to interrupt mmu-miR-132 results in T cell lymphomas [77,78]. Located a little further distal on chr.…”