The molecular scaffold kinase suppressor of Ras 1 is a modifier of RasV12-induced and replicative senescence

Molecular and Cellular Biology
Robert L KortumRobert E Lewis

Abstract

In primary mouse embryo fibroblasts (MEFs), oncogenic Ras induces growth arrest via Raf/MEK/extracellular signal-regulated kinase (ERK)-mediated activation of the p19ARF/p53 and INK4/Rb tumor suppressor pathways. Ablation of these same pathways causes spontaneous immortalization in MEFs, and oncogenic transformation by Ras requires ablation of one or both of these pathways. We show that Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK cascade, is necessary for RasV12-induced senescence, and its disruption enhances primary MEF immortalization. RasV12 failed to induce p53, p19ARF, p16INK4a, and p15INK4b expression in KSR1-/- MEFs and increased proliferation instead of causing growth arrest. Reintroduction of wild-type KSR1, but not a mutated KSR1 construct unable to bind activated ERK, rescued RasV12-induced senescence. On continuous culture, deletion of KSR1 accelerated the establishment of spontaneously immortalized cultures and increased the proportion of cultures escaping replicative crisis. Despite enhancing escape from both RasV12-induced and replicative senescence, however, both primary and immortalized KSR1-/- MEFs are completely resistant to RasV12-induced transformation. These data show that e...Continue Reading

References

Jan 1, 1987·Annual Review of Biochemistry·M Barbacid
Jun 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·C J DerG M Cooper
Jul 1, 1983·Proceedings of the National Academy of Sciences of the United States of America·U R RappJ R Stephenson
Sep 26, 1995·Proceedings of the National Academy of Sciences of the United States of America·G P DimriO Pereira-Smith
Mar 15, 1994·Proceedings of the National Academy of Sciences of the United States of America·J A PietenpolB Vogelstein
Nov 19, 1993·Cell·W S el-DeiryB Vogelstein
Jul 1, 1993·Genes & Development·X WuA J Levine
May 1, 1996·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·K D LindorA R Zinsmeister
Nov 26, 1996·Proceedings of the National Academy of Sciences of the United States of America·S N JonesA Bradley
Sep 1, 1997·Molecular and Cellular Biology·A SewingH Land
Dec 16, 1997·Proceedings of the National Academy of Sciences of the United States of America·N R MichaudD K Morrison
Jul 22, 1998·Proceedings of the National Academy of Sciences of the United States of America·C P WebbG F Vande Woude
Sep 23, 1998·Nature·I PalmeroM Serrano
Oct 9, 1998·Genes & Development·J ZhuJ M Bishop
Jun 5, 1999·Carcinogenesis·L I Huschtscha, R R Reddel
Jul 27, 1999·The Journal of Biological Chemistry·H Gille, J Downward
Mar 9, 2000·Nature Cell Biology·A CarneroD H Beach
Mar 14, 2000·Current Opinion in Cell Biology·W R Burack, A S Shaw
Mar 25, 2000·Molecular and Cellular Biology·M MalumbresA Pellicer
Jun 28, 2001·Proceedings of the National Academy of Sciences of the United States of America·R M AlaniC B Shifflett
Sep 21, 2001·Molecular and Cellular Biology·W WeiJ M Sedivy
Oct 11, 2001·Proceedings of the National Academy of Sciences of the United States of America·A KrtolicaJ Campisi
Oct 31, 2001·Trends in Cell Biology·J Campisi

❮ Previous
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Citations

Jul 29, 2008·Cancer Chemotherapy and Pharmacology·Scott M Stoeger, Kenneth H Cowan
Feb 4, 2012·Cell Death and Differentiation·M W Gramling, C M Eischen
Jan 17, 2009·The Journal of Biological Chemistry·Gina L RazidloRobert E Lewis
Jul 18, 2012·Molecular and Cellular Biology·Mario R FernandezRobert E Lewis
Jul 23, 2011·Genes & Cancer·David MatallanasWalter Kolch
Dec 30, 2011·PloS One·Paula J KluthoRobert E Lewis
Aug 10, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jason W LocasaleArup K Chakraborty
Jul 4, 2012·Cellular and Molecular Life Sciences : CMLS·Isabel F FernándezPedro A Lazo
Mar 28, 2013·Cellular and Molecular Life Sciences : CMLS·Guido TaroneMara Brancaccio
Feb 15, 2012·Cellular Signalling·Hua ZhangGeorgios Giamas
Jun 8, 2012·Cell Cycle·Tatiana V PospelovaMikhail V Blagosklonny
Apr 25, 2015·Nature Reviews. Molecular Cell Biology·Hugo Lavoie, Marc Therrien
Nov 4, 2009·Cell Metabolism·Diane L Costanzo-GarveyRobert E Lewis
Mar 4, 2015·Molecular Immunology·Alex M AbelSubramaniam Malarkannan
Mar 24, 2017·Expert Opinion on Therapeutic Targets·Beth K NeilsenKurt W Fisher
Mar 5, 2013·International Journal of Molecular Sciences·Melanie MeisterRitva Tikkanen
Jun 9, 2016·Molecular and Cellular Biology·Jamie L McCallRobert E Lewis
Oct 14, 2017·F1000Research·Danielle FrodymaRobert Lewis
Oct 21, 2006·Biochemical Society Transactions·D B Sacks
Aug 6, 2020·International Journal of Molecular Sciences·Pui-Kei WuJong-In Park

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