Abstract
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 Eμ-myc transgenic mice. Mdm2+/-Eμ-myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild-type transgenic littermates. Impaired lymphoma development was associated with drastic reductions in peripheral B cell numbers in Mdm2+/-Eμ-myc transgenics, and primary pre-B cells from Mdm2+/-Eμ-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+/-Eμ-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.
Original language | English (US) |
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Pages (from-to) | 1442-1450 |
Number of pages | 9 |
Journal | EMBO Journal |
Volume | 22 |
Issue number | 6 |
DOIs | |
State | Published - Mar 17 2003 |
Keywords
- Apoptosis
- Lymphoma
- Mdm2
- Myc
- P53
ASJC Scopus subject areas
- Neuroscience(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)