A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling.
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 of cyclin 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 p19(ARF)-p53 pathway.
Shvarts
Avi
A
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Brummelkamp
Thijn R
TR
Scheeren
Ferenc
F
Koh
Eugene
E
Daley
George Q
GQ
Spits
Hergen
H
Bernards
René
R
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1