Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF
AUTOR(ES)
Jacobs, Jacqueline J.L.
FONTE
Cold Spring Harbor Laboratory Press
RESUMO
The bmi-1 and myc oncogenes collaborate strongly in murine lymphomagenesis, but the basis for this collaboration was not understood. We recently identified the ink4a–ARF tumor suppressor locus as a critical downstream target of the Polycomb-group transcriptional repressor Bmi-1. Others have shown that part of Myc's ability to induce apoptosis depends on induction of p19arf. Here we demonstrate that down-regulation of ink4a–ARF by Bmi-1 underlies its ability to cooperate with Myc in tumorigenesis. Heterozygosity for bmi-1 inhibits lymphomagenesis in Eμ–myc mice by enhancing c-Myc-induced apoptosis. We observe increased apoptosis in bmi-1−/− lymphoid organs, which can be rescued by deletion of ink4a–ARF or overexpression of bcl2. Furthermore, Bmi-1 collaborates with Myc in enhancing proliferation and transformation of primary embryo fibroblasts (MEFs) in an ink4a–ARF dependent manner, by prohibiting Myc-mediated induction of p19arf and apoptosis. We observe strong collaboration between the Eμ–myc transgene and heterozygosity for ink4a–ARF, which is accompanied by loss of the wild-type ink4a–ARF allele and formation of highly aggressive B-cell lymphomas. Together, these results reinforce the critical role of Bmi-1 as a dose-dependent regulator of ink4a–ARF, which on its turn acts to prevent tumorigenesis on activation of oncogenes such as c-myc.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=317101Documentos Relacionados
- Transcriptional Coactivator Cited2 Induces Bmi1 and Mel18 and Controls Fibroblast Proliferation via Ink4a/ARF
- c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines.
- Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice
- Ink4a/Arf expression is a biomarker of aging
- Ornithine decarboxylase is a mediator of c-Myc-induced apoptosis.