Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis
AUTOR(ES)
Alt, Jodi R.
FONTE
Oxford University Press
RESUMO
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. Im paired 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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=151074Documentos Relacionados
- Disruption of the ARF–Mdm2–p53 tumor suppressor pathway in Myc-induced lymphomagenesis
- BAG-1 haplo-insufficiency impairs lung tumorigenesis
- Apoptosis Triggered by Myc-Induced Suppression of Bcl-XL or Bcl-2 Is Bypassed during Lymphomagenesis
- Id2 Is Dispensable for Myc-Induced Epidermal Neoplasia
- Bax Loss Impairs Myc-Induced Apoptosis and Circumvents the Selection of p53 Mutations during Myc-Mediated Lymphomagenesis