Home LiteratureArticle Details
PMID: 10541554 Published · ppublish English Journal Article

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

Genes & development ·Vol. 13 ·No. 20 ·1999-10-15 ·Pages 2678-90

Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M

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.

MeSH Terms
Animals Apoptosis/genetics Cell Transformation, Neoplastic/genetics Cells, Cultured Cocarcinogenesis Down-Regulation Female Gene Expression Genes, bcl-2 Genes, myc Genes, p16 Heterozygote Lymphoma, B-Cell/etiology,genetics,pathology Male Mice Mice, Knockout Mice, Mutant Strains Nuclear Proteins/genetics Polycomb Repressive Complex 1 Proteins/genetics Proto-Oncogene Proteins/genetics Repressor Proteins Tumor Suppressor Protein p14ARF
Chemicals
Bmi1 protein, mouse Nuclear Proteins Proteins Proto-Oncogene Proteins Repressor Proteins Tumor Suppressor Protein p14ARF Polycomb Repressive Complex 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Jacobs J J
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Scheijen B
Voncken J W
Kieboom K
Berns A
van Lohuizen M
References (55)
55 references, click to expand
  1. Apoptotic cell death induced by c-myc is inhibited by bcl-2.
    Nature. 1992 Oct 8;359(6395):552-4 PMID: 1406975
  2. Cellular memory of transcriptional states by Polycomb-group proteins.
    Semin Cell Dev Biol. 1999 Apr;10(2):227-35 PMID: 10441076
  3. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice.
    Genes Dev. 1993 Apr;7(4):671-82 PMID: 8458579
  4. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis.
    Genes Dev. 1999 Oct 15;13(20):2658-69 PMID: 10541552
  5. Nucleolar Arf sequesters Mdm2 and activates p53.
    Nat Cell Biol. 1999 May;1(1):20-6 PMID: 10559859
  6. Infection of preimplantation mouse embryos and of newborn mice with leukemia virus: tissue distribution of viral DNA and RNA and leukemogenesis in the adult animal.
    Proc Natl Acad Sci U S A. 1975 Oct;72(10):4008-12 PMID: 1060083
  7. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes.
    Nature. 1983 Aug 18-24;304(5927):596-602 PMID: 6308472
  8. The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice.
    Cell. 1986 Oct 10;47(1):11-8 PMID: 3093082
  9. The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells.
    J Exp Med. 1988 Feb 1;167(2):353-71 PMID: 3258007
  10. Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population.
    Mol Cell Biol. 1990 May;10(5):1901-7 PMID: 2183011
  11. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2.
    Nature. 1990 Nov 22;348(6299):331-3 PMID: 2250704
  12. Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally.
    Mol Cell Biol. 1991 Feb;11(2):1176-9 PMID: 1990273
  13. Abnormalities of the immune system induced by dysregulated bcl-2 expression in transgenic mice.
    Curr Top Microbiol Immunol. 1990;166:175-81 PMID: 2073796
  14. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging.
    Cell. 1991 May 31;65(5):737-52 PMID: 1904008
  15. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice.
    Cell. 1991 May 31;65(5):753-63 PMID: 1904009
  16. Induction of apoptosis in fibroblasts by c-myc protein.
    Cell. 1992 Apr 3;69(1):119-28 PMID: 1555236
  17. bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis.
    Oncogene. 1993 Nov;8(11):3161-4 PMID: 8414519
  18. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
    Nature. 1993 Dec 16;366(6456):704-7 PMID: 8259215
  19. Mediation of c-Myc-induced apoptosis by p53.
    Science. 1994 Sep 30;265(5181):2091-3 PMID: 8091232
  20. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene.
    Genes Dev. 1994 Apr 1;8(7):757-69 PMID: 7926765
  21. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1.
    Genes Dev. 1994 Dec 1;8(23):2817-30 PMID: 7995520
  22. Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss.
    Oncogene. 1995 May 4;10(9):1717-23 PMID: 7753548
  23. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins.
    Nucleic Acids Res. 1995 May 25;23(10):1686-90 PMID: 7784172
  24. Evidence that c-myc mediated apoptosis does not require wild-type p53 during lymphomagenesis.
    Oncogene. 1995 Jul 6;11(1):175-9 PMID: 7624125
  25. The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice.
    Oncogene. 1995 Jul 6;11(1):181-90 PMID: 7624126
  26. c-Myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanisms.
    Oncogene. 1995 Dec 7;11(11):2411-8 PMID: 8570193
  27. Role of the INK4a locus in tumor suppression and cell mortality.
    Cell. 1996 Apr 5;85(1):27-37 PMID: 8620534
  28. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant.
    EMBO J. 1996 Feb 15;15(4):827-38 PMID: 8631304
  29. Proteins of the Myc network: essential regulators of cell growth and differentiation.
    Adv Cancer Res. 1996;68:109-82 PMID: 8712067
  30. Anchorage-dependent cell cycle progression.
    J Cell Biol. 1997 Jan 13;136(1):1-4 PMID: 9026502
  31. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB.
    Nature. 1997 Feb 6;385(6616):544-8 PMID: 9020362
  32. Upregulation of endogenous p53 and induction of in vivo apoptosis in B-lineage lymphomas of E(mu)-myc transgenic mice by deregulated c-myc transgene.
    Mol Carcinog. 1997 Feb;18(2):66-77 PMID: 9049182
  33. Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/- mice.
    Cell. 1997 Jun 27;89(7):1011-9 PMID: 9215624
  34. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice.
    Cell. 1997 Jun 27;89(7):1033-41 PMID: 9215626
  35. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging.
    Oncogene. 1997 Jul 10;15(2):203-11 PMID: 9244355
  36. Loss of matrix adhesion triggers rapid transformation-selective apoptosis in fibroblasts.
    J Cell Biol. 1997 Aug 25;138(4):901-11 PMID: 9265655
  37. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmi1 transgenic mice require the Bmi1 RING finger.
    Oncogene. 1997 Aug 18;15(8):899-910 PMID: 9285685
  38. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis.
    Science. 1997 Nov 14;278(5341):1305-9 PMID: 9360929
  39. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF.
    Cell. 1997 Nov 28;91(5):649-59 PMID: 9393858
  40. Functional analysis of mouse Polycomb group genes.
    Cell Mol Life Sci. 1998 Jan;54(1):71-9 PMID: 9487388
  41. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53.
    Cell. 1998 Mar 20;92(6):713-23 PMID: 9529248
  42. The molecular role of Myc in growth and transformation: recent discoveries lead to new insights.
    FASEB J. 1998 Jun;12(9):633-51 PMID: 9619443
  43. Myc/p53 interactions in transgenic mouse mammary development, tumorigenesis and chromosomal instability.
    Oncogene. 1998 May 28;16(21):2755-66 PMID: 9652742
  44. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization.
    Genes Dev. 1998 Aug 1;12(15):2424-33 PMID: 9694806
  45. E1A signaling to p53 involves the p19(ARF) tumor suppressor.
    Genes Dev. 1998 Aug 1;12(15):2434-42 PMID: 9694807
  46. A matter of life and cell death.
    Science. 1998 Aug 28;281(5381):1317-22 PMID: 9721090
  47. Tumor surveillance via the ARF-p53 pathway.
    Genes Dev. 1998 Oct 1;12(19):2984-91 PMID: 9765200
  48. The p16INK4a/CDKN2A tumor suppressor and its relatives.
    Biochim Biophys Acta. 1998 Oct 14;1378(2):F115-77 PMID: 9823374
  49. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus.
    Nature. 1999 Jan 14;397(6715):164-8 PMID: 9923679
  50. The INK4A/ARF locus and its two gene products.
    Curr Opin Genet Dev. 1999 Feb;9(1):22-30 PMID: 10072356
  51. Transient excess of MYC activity can elicit genomic instability and tumorigenesis.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3940-4 PMID: 10097142
  52. Mechanisms of apoptosis by c-Myc.
    Oncogene. 1999 May 13;18(19):2967-87 PMID: 10378693
  53. MYC oncogenes and human neoplastic disease.
    Oncogene. 1999 May 13;18(19):3004-16 PMID: 10378696
  54. The trithorax-group and polycomb-group chromatin modifiers: implications for disease.
    Curr Opin Genet Dev. 1999 Jun;9(3):355-61 PMID: 10377289
  55. Cooperative interaction between c-myc and bcl-2 proto-oncogenes.
    Nature. 1992 Oct 8;359(6395):554-6 PMID: 1406976
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.13.20.2678
Published
1999-10-15
Pages
2678-90
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC317101
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.13.20.2678 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2