Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Disruption of E2F signaling suppresses the INK4a-induced proliferative defect in M33-deficient mice

Oncogene volume 23, pages 7660–7668 (2004)Cite this article

Abstract

Polycomb group (Pc-G) proteins associate to form large complexes that repress Hox genes, thereby imposing Hox gene expression pattern required for development. However, Pc-G proteins have a Hox-independent function in controlling cell proliferation. Here we show that embryonic fibroblasts derived from M33-deficient mice are impaired in the progression into the S phase of the cell cycle, as shown by a reduced rate of incorporation of bromodeoxyuridine. These cells have a senescent phenotype, associated to an abnormal accumulation of the cyclin-dependent kinase inhibitor p16INK4a protein. We demonstrate that this defect is bypassed in mutant embryonic fibroblasts expressing a transdominant negative form of the cell cycle controlling transcription factor E2F (E2F-DB). In addition, we show that the polycomb protein M33 controls critical expansion of B- and T-lymphocyte precursors. Together, our results emphasize M33-Polycomb protein function in cell cycle control.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Akashi K, Kondo M, von Freeden-Jeffry U, Murray R and Weissman IL . (1997). Cell, 89, 1033–1041.

  • Alkema MJ, Bronk M, Verhoeven E, Otte A, van't Veer LJ, Berns A and van Lohuizen M . (1997a). Genes Dev., 11, 226–240.

  • Alkema MJ, Jacobs H, van Lohuizen M and Berns A . (1997b). Oncogene, 15, 899–910.

  • Alkema MJ, Jacobs J, Voncken JW, Jenkins NA, Copeland NG, Satijn DP, Otte AP, Berns A and van Lohuizen M . (1997c). J. Mol. Biol., 273, 993–1003.

  • Bel S, CorĂ© N, Djabali M, Kieboom K, Van der Lugt N, Alkema MJ and Van Lohuizen M . (1998). Development, 125, 3543–3551.

  • CorĂ© N, Bel S, Gaunt SJ, Aurrand-Lions M, Pearce J, Fisher A and Djabali M . (1997). Development, 124, 721–729.

  • Dahiya A, Wong S, Gonzalo S, Gavin M and Dean DC . (2001). Mol. Cell, 8, 557–569.

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M and Campisi J . (1995). Proc. Natl. Acad. Sci. USA, 92, 9363–9367.

  • Godfrey DI and Zlotnik A . (1993). Immunol. Today, 14, 547–553.

  • Gould A . (1997). Curr. Opin. Genet. Dev., 7, 488–494.

  • Hardy RR, Carmack CE, Shinton SA, Kemp JD and Hayakawa K . (1991). J. Exp. Med., 173, 1213–1225.

  • Helin K and Harlow E . (1994). J. Virol., 68, 5027–5035.

  • Jacobs JJ and van Lohuizen M . (2002). Biochim. Biophys. Acta, 1602, 151–161.

  • Jacobs JJ, Kieboom K, Marino S, DePinho RA and van Lohuizen M . (1999a). Nature, 397, 164–168.

  • Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A and van Lohuizen M . (1999b). Genes Dev., 13, 2678–2690.

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G and Sherr CJ . (1997). Cell, 91, 649–659.

  • Kondo M, Akashi K, Domen J, Sugamura K and Weissman IL . (1997). Immunity, 7, 155–162.

  • Krimpenfort P, Quon KC, Mooi WJ, Loonstra A and Berns A . (2001). Nature, 413, 83–86.

  • Lessard J, Schumacher A, Thorsteinsdottir U, van Lohuizen M, Magnuson T and Sauvageau G . (1999). Genes Dev., 13, 2691–2703.

  • Lukas J, Petersen BO, Holm K, Bartek J and Helin K . (1996). Mol. Cell. Biol., 16, 1047–1057.

  • Maraskovsky E, O’Reilly LA, Teepe M, Corcoran LM, Peschon JJ and Strasser A . (1997). Cell, 89, 1011–1019.

  • Ohta H, Sawada A, Kim JY, Tokimasa S, Nishiguchi S, Humphries RK, Hara J and Takihara Y . (2002). J. Exp. Med., 195, 759–770.

  • Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ and Clarke MF . (2003). Nature, 423, 302–305.

  • Penit C, Lucas B and Vasseur F . (1995). J. Immunol., 154, 5103–5113.

  • Pirrotta V . (1995). Curr. Opin. Genet. Dev., 5, 466–472.

  • Rowland BD, Denissov SG, Douma S, Stunnenberg HG, Bernards R and Peeper DS . (2002). Cancer Cell, 2, 55–65.

  • Scollay R . (1991). Curr. Opin. Immunol., 3, 204–209.

  • Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW . (1997). Cell, 88, 593–602.

  • Sherr CJ . (2001). Nat. Rev. Mol. Cell Biol., 2, 731–737.

  • Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S and Harris AW . (1991). Proc. Natl. Acad. Sci. USA, 88, 8661–8665.

  • Tetsu O, Ishihara H, Kanno R, Kamiyasu M, Inoue H, Tokuhisa T, Taniguchi M and Kanno M . (1998). Immunity, 9, 439–448.

  • Veis DJ, Sentman CL, Bach EA and Korsmeyer SJ . (1993). J. Immunol., 151, 2546–2554.

  • Wyllie AH . (1980). Nature, 284, 555–556.

  • Zhang HS, Postigo AA and Dean DC . (1999). Cell, 97, 53–61.

  • Zindy F, Quelle DE, Roussel MF and Sherr CJ . (1997). Oncogene, 15, 203–211.

Download references

Acknowledgements

We are grateful to D Dean for providing the pCMVE2F1(1–374) plasmid, to M Malissen for the EμSV-Bcl-2-25 mouse strain, to R Schotte and M Naspetti for the LZRS-ires-GFP retroviral vector. We thank M Barad and N Brun for their technical help with FACS and cell sorting. This work was supported by grants from CNRS, ARC, LNCC and Fondation de France.

Author information

Authors and Affiliations

  1. Centre d'Immunologie INSERM/CNRS, Case 906, Marseille, Cedex 9, 13288, France

    Nathalie Coré, Florence Joly, Annie Boned & Malek Djabali

Authors
  1. Nathalie Coré
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florence Joly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annie Boned
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Malek Djabali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Malek Djabali.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coré, N., Joly, F., Boned, A. et al. Disruption of E2F signaling suppresses the INK4a-induced proliferative defect in M33-deficient mice. Oncogene 23, 7660–7668 (2004). https://doi.org/10.1038/sj.onc.1207998

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207998

Keywords

This article is cited by

Search

Advanced search

Quick links