A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling

Genes & Development
Avi ShvartsRené Bernards

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 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.

References

Jul 9, 1996·Proceedings of the National Academy of Sciences of the United States of America·C C ChangR Dalla-Favera
Jun 27, 1998·Biochemical and Biophysical Research Communications·S Bajalica-LagercrantzJ Lagercrantz
Sep 23, 1998·Nature·S BatesK H Vousden
Jan 19, 2000·The Journal of Experimental Medicine·L M Staudt
Apr 14, 2000·Oncogene·C Y Dai, G H Enders
Aug 31, 2000·Cell·C J Sherr, R A DePinho
Aug 2, 2001·Proceedings of the National Academy of Sciences of the United States of America·D H RandleM F Roussel
Feb 2, 2002·Nature·Laura J van 't VeerStephen H Friend

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Citations

Jun 11, 2010·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·Mar Vergel, Amancio Carnero
Jan 27, 2004·The American Journal of Pathology·Ana-Isabel SáezMiguel A Piris
Aug 23, 2002·Seminars in Cancer Biology·Mikael S Lindström, Klas G Wiman
Jan 20, 2010·Nature Immunology·Shane CrottyStephen P Schoenberger
Aug 18, 2006·Nature Reviews. Cancer·Charles J Sherr
Mar 28, 2008·Proceedings of the National Academy of Sciences of the United States of America·Shuying LiuGordon B Mills
Dec 5, 2012·The Journal of Biological Chemistry·Nobuhide TsuruokaTakeshi Tokuhisa
Apr 4, 2007·The Journal of Experimental Medicine·Tracy C KuoKathryn Calame
May 26, 2010·The Journal of Experimental Medicine·Cihangir DuyMarkus Müschen
Feb 19, 2005·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Eric R JamesLorie L Robertson
Dec 20, 2002·Nucleic Acids Research·Eugene Y KohGeorge Q Daley
Aug 25, 2005·Cold Spring Harbor Symposia on Quantitative Biology·T R BrummelkampR L Beijersbergen
Jul 28, 2006·Cold Spring Harbor Symposia on Quantitative Biology·T F WestbrookS J Elledge
Oct 23, 2002·Molecular and Cellular Biology·Marc SchmidtRené H Medema
Dec 30, 2009·The Journal of Clinical Investigation·Taco W KuijpersRené A W van Lier
Nov 28, 2013·PloS One·Jingwen ChenYu-Sheng Cong
Dec 18, 2013·Trends in Immunology·Srividya SwaminathanMarkus Müschen
Oct 12, 2013·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Peir-In LiangChing-Yih Lin
Jul 16, 2005·Hematology·Fabrice Jardin, Surinder S Sahota
Jan 7, 2006·Leukemia & Lymphoma·Maria BaiPanagiotis Kanavaros
Aug 22, 2006·Scandinavian Journal of Immunology·K-P Nera, O Lassila
Apr 21, 2006·Immunological Reviews·Arthur L ShafferLouis M Staudt
Nov 19, 2010·British Journal of Haematology·Simon D WagnerPaul Ko Ferrigno
Nov 21, 2009·The EMBO Journal·Nicolas HumbertDavid Bernard
Dec 8, 2010·The Biochemical Journal·Jia ShenChuangui Wang
Nov 3, 2004·The Journal of Clinical Investigation·Ande Satyanarayana, K Lenhard Rudolph
Dec 4, 2002·Nature Reviews. Immunology·A L ShafferLouis M Staudt
Dec 30, 2014·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ashwini S Phadnis-MogheNorbert E Kaminski

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