| First Author | Kadariya Y | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 6 | Pages | e67635 |
| PubMed ID | 23840755 | Mgi Jnum | J:203713 |
| Mgi Id | MGI:5528585 | Doi | 10.1371/journal.pone.0067635 |
| Citation | Kadariya Y, et al. (2013) Germline Mutations in Cooperate with to Accelerate Tumorigenesis in Mice. PLoS One 8(6):e67635 |
| abstractText | OBJECTIVE: The gene encoding the methionine salvage pathway methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene that is frequently inactivated in a wide variety of human cancers. In this study, we have examined if heterozygosity for a null mutation in Mtap (MtaplacZ) could accelerate tumorigenesis development in two different mouse cancer models, Emu-myc transgenic and Pten+/- . METHODS: Mtap Emu-myc and Mtap Pten mice were generated and tumor-free survival was monitored over time. Tumors were also examined for a variety of histological and protein markers. In addition, microarray analysis was performed on the livers of MtaplacZ/+ and Mtap +/+ mice. RESULTS: Survival in both models was significantly decreased in MtaplacZ/+ compared to Mtap+/+ mice. In Emicro-myc mice, Mtap mutations accelerated the formation of lymphomas from cells in the early pre-B stage, and these tumors tended to be of higher grade and have higher expression levels of ornithine decarboxylase compared to those observed in control Emicro-myc Mtap+/+ mice. Surprisingly, examination of Mtap status in lymphomas in Emicro-myc MtaplacZ/+ and Emicro-myc Mtap+/+ animals did not reveal significant differences in the frequency of loss of Mtap protein expression, despite having shorter latency times, suggesting that haploinsufficiency of Mtap may be playing a direct role in accelerating tumorigenesis. Consistent with this idea, microarray analysis on liver tissue from age and sex matched Mtap+/+ and MtaplacZ/+ animals found 363 transcripts whose expression changed at least 1.5-fold (P<0.01). Functional categorization of these genes reveals enrichments in several pathways involved in growth control and cancer. CONCLUSION: Our findings show that germline inactivation of a single Mtap allele alters gene expression and enhances lymphomagenesis in Emicro-myc mice. |
