Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF

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 th...

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Bibliographic Details
Published in:Genes & development 1999-10, Vol.13 (20), p.2678-2690
Main Authors: Jacobs, J J, Scheijen, B, Voncken, J W, Kieboom, K, Berns, A, van Lohuizen, M
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
ARF protein
Bmi-1 protein
c-Myc protein
Cell Transformation, Neoplastic - genetics
Cells, Cultured
Cocarcinogenesis
Down-Regulation
Female
Gene Expression
Genes, bcl-2
Genes, myc
Genes, p16
Heterozygote
INK4a protein
lymphoma
Lymphoma, B-Cell - etiology
Lymphoma, B-Cell - genetics
Lymphoma, B-Cell - pathology
Male
Mice
Mice, Knockout
Mice, Mutant Strains
Nuclear Proteins - genetics
Polycomb Repressive Complex 1
Proteins - genetics
Proto-Oncogene Proteins - genetics
Repressor Proteins
Research Paper
Tumor Suppressor Protein p14ARF
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Summary: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 Emu-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 Emu-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.
ISSN:0890-9369
DOI:10.1101/gad.13.20.2678