A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19ARF–p53 signaling

  1. Avi Shvarts1,4,
  2. Thijn R. Brummelkamp1,4,
  3. Ferenc Scheeren2,
  4. Eugene Koh3,
  5. George Q. Daley3,
  6. Hergen Spits2, and
  7. René Bernards1,5
  1. Divisions of 1Molecular Carcinogenesis and 2Immunology and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 3Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA

Abstract

Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries, we identify BCL6 as a potent inhibitor of senescence.BCL6 is frequently activated in non-Hodgkin's lymphoma, but its mechanism of action has remained unclear. BCL6 efficiently immortalizes primary mouse embryonic fibroblasts and cooperates with RAS in oncogenic transformation. BCL6 overrides the senescence response downstream of p53 through a process that requires induction ofcyclin D1 expression, as cyclin D1 knockout fibroblasts are specifically resistant to BCL6 immortalization. We show that BCL6 expression also dramatically extends the replicative lifespan of primary human B cells in culture and induces cyclin D1 expression, indicating that BCL6 has a similar activity in lymphoid cells. Our results suggest that BCL6 contributes to oncogenesis by rendering cells unresponsive to antiproliferative signals from the p19ARF–p53 pathway.

Keywords

Footnotes

  • 4 These authors contributed equally to this work.

  • 5 Corresponding author.

  • E-MAIL bernards{at}nki.nl; FAX 31-20-512-1954.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.929302.

    • Received July 18, 2001.
    • Accepted January 22, 2002.
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