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

• Published in: Genes & development Vol. 13; no. 20; pp. 2678 - 2690
• Main Authors: Jacobs, J J, Scheijen, B, Voncken, J W, Kieboom, K, Berns, A, van Lohuizen, M
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 15-10-1999
• 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
• ISSN: 0890-9369
• DOI: 10.1101/gad.13.20.2678

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.