Germline Mutations in Mtap Cooperate with Myc to Accelerate Tumorigenesis in MiceReportar como inadecuado




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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, Eμ-myc transgenic and Pten+-−.

Methods

Mtap Eμ-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 Eµ-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 Eµ-myc Mtap+-+ mice. Surprisingly, examination of Mtap status in lymphomas in Eµ-myc MtaplacZ-+ and Eµ-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 Eµ-myc mice.



Autor: Yuwaraj Kadariya, Baiqing Tang, Liqun Wang, Tahseen Al-Saleem, Kyoko Hayakawa, Michael J. Slifker, Warren D. Kruger

Fuente: http://plos.srce.hr/



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