| First Author | Alt JR | Year | 2003 |
| Journal | EMBO J | Volume | 22 |
| Issue | 6 | Pages | 1442-50 |
| PubMed ID | 12628936 | Mgi Jnum | J:82477 |
| Mgi Id | MGI:2653386 | Doi | 10.1093/emboj/cdg133 |
| Citation | Alt JR, et al. (2003) Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J 22(6):1442-50 |
| abstractText | Mdm2 harnesses the p53 tumor suppressor, yet loss of one Mdm2 allele in Mdm2(+/-) mice has heretofore not been shown to impair tumor development. Here we report that Mdm2 haplo-insufficiency profoundly suppresses lymphomagenesis in E micro -myc transgenic mice. Mdm2(+/-)E micro -myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild-type transgenic littermates. Im paired lymphoma development was associated with drastic reductions in peripheral B cell numbers in Mdm2(+/-)E micro -myc transgenics, and primary pre-B cells from Mdm2(+/-)E micro -myc transgenics and Mdm2(+/-) littermates were extremely susceptible to spontaneous apoptosis. Loss of p53 rescued all of the effects of Mdm2 haplo-insufficiency, indicating they were p53 dependent. Furthermore, half of the lymphomas that ultimately emerged in Mdm2(+/-)E micro -myc transgenics harbored inactivating mutations in p53, and the majority overcame haplo-insufficiency by overexpressing Mdm2. These results support the concept that Mdm2 functions are rate limiting in lymphomagenesis and that targeting Mdm2 will enhance p53-mediated apoptosis, compromising tumor development and/or maintenance. |
