title: Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF.
abstract: 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.
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Jacobs
authors.forename: B
authors.initials: B
authors.lastname: Scheijen
authors.forename: J W
authors.initials: JW
authors.lastname: Voncken
authors.forename: K
authors.initials: K
authors.lastname: Kieboom
authors.forename: A
authors.initials: A
authors.lastname: Berns
authors.forename: M
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D003043:Cocarcinogenesis; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D019254:Genes, bcl-2; D016259:Genes, myc; D019942:Genes, p16; D006579:Heterozygote; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics*; D063150:Polycomb Repressive Complex 1; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF
chemical_list: C489421:Bmi1 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF; D063150:Polycomb Repressive Complex 1