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The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus

Nature volume 397, pages 164–168 (1999)Cite this article

Abstract

The bmi-1 gene was first isolated as an oncogene that cooperates with c-myc in the generation of mouse lymphomas1,2. We subsequently identified Bmi-1 as a transcriptional repressor belonging to the mouse Polycomb group3,4,5,6. The Polycomb group comprises an important, conserved set of proteins that are required to maintain stable repression of specific target genes, such as homeobox-cluster genes, during development7,8,9. In mice, the absence of bmi-1 expression results in neurological defects and severe proliferative defects in lymphoid cells, whereas bmi-1 overexpression induces lymphomas4,10. Here we show that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence. In these fibroblasts and in bmi-1-deficient lymphocytes, the expression of the tumour suppressors p16 and p19Arf, which are encoded by ink4a, is raised markedly. Conversely, overexpression of bmi-1 allows fibroblast immortalization, downregulates expression of p16 and p19Arf and, in combination with H-ras, leads to neoplastic transformation. Removal of ink4a dramatically reduces the lymphoid and neurological defects seen in bmi-1-deficient mice, indicating that ink4a is a critical in vivo target for Bmi-1. Our results connect transcriptional repression by Polycomb-group proteins with cell-cycle control and senescence.

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Figure 1: Impaired proliferation of bmi-1−/− MEFs is rescued by wild-type but not mutant bmi-1.
Figure 2: Effects of absence or overexpression of bmi-1 on cell-cycle-regulatory proteins in primary fibroblasts.
Figure 3: p15, p16 and p19Arf mRNA levels in bmi-1+/+, bmi-1−/− and bmi-1+/− MEFs and in mel-18+/+ and mel-18 −/− MEFs.
Figure 4: p15, p16 and p19Arf mRNA levels in bmi-1+/+ and bmi-1−/− splenocytes and control or bmi-1-virus-infected MEFs, and cooperation between Ras and Bmi-1 in neoplastic transformation.
Figure 5: Rescue of bmi-1−/−-associated proliferative defects in bmi-1−/− ink4a−/− mice and MEFs.

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Acknowledgements

We thank G. Peters for p16 and p15 cDNA plasmids; H. Koseki and J. Deschamps for mel-18−/− embryos; T. Ide for the TiG-3 cells; J. Sedivy for c-myc−/− TGR-1 cells; S. Lowe, B. Amati, C. Sherr, M. Ewen, D. Peeper and R. Bernards for gifts of recombinant retroviral vectors; G. Nolan for providing phoenix eco- and amphotropic packaging cell lines and LZRS-IRES-EGFP retroviral vectors; N. van der Lugt for constructing the LZRS-bmi-1-IRES-EGFP retrovirus; E. de Pauw for telomere FISH analysis; and R. Bernards, A. Berns and W. Voncken for critically reading the manuscript J.J.L.J. and K.K. were supported by a grant of the Dutch Cancer Society (K.W.F.)

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Authors and Affiliations

  1. Division of Molecular Carcinogenesis The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Jacqueline J. L. Jacobs, Karin Kieboom & Maarten van Lohuizen

  2. Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Silvia Marino

  3. Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street (M463), Boston , 02115, Massachusetts, USA

    Ronald A DePinho

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Correspondence to Maarten van Lohuizen.

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Jacobs, J., Kieboom, K., Marino, S. et al. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999). https://doi.org/10.1038/16476

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