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Kadariya Y , Tang B , Wang L , Al-Saleem T , Hayakawa K , Slifker MJ , Kruger WD
Germline Mutations in Mtap Cooperate with Myc to Accelerate Tumorigenesis in Mice
PLoS One. 2013 ;8(6) :e67635
PMID: 23840755   
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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.
Kadariya, Yuwaraj Tang, Baiqing Wang, Liqun Al-Saleem, Tahseen Hayakawa, Kyoko Slifker, Michael J Kruger, Warren D PloS one PLoS One. 2013 Jun 26;8(6):e67635. Print 2013.