Tumorigenic activity and therapeutic inhibition of Rheb GTPase.

Genes & Development
Konstantinos J MavrakisHans-Guido Wendel

Abstract

The AKT-mTOR pathway harbors several known and putative oncogenes and tumor suppressors. In a phenotypic screen for lymphomagenesis, we tested candidate genes acting upstream of and downstream from mTOR in vivo. We find that Rheb, a proximal activator of mTORC1, can produce rapid development of aggressive and drug-resistant lymphomas. Rheb causes mTORC1-dependent effects on apoptosis, senescence, and treatment responses that resemble those of Akt. Moreover, Rheb activity toward mTORC1 requires farnesylation and is readily blocked by a pharmacological inhibitor of farnesyltransferase (FTI). In Pten-deficient tumor cells, inhibition of Rheb by FTI is responsible for the drug's anti-tumor effects, such that a farnesylation-independent mutant of Rheb renders these tumors resistant to FTI therapy. Notably, RHEB is highly expressed in some human lymphomas, resulting in mTORC1 activation and increased sensitivity to rapamycin and FTI. Downstream from mTOR, we examined translation initiation factors that have been implicated in transformation in vitro. Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of far...Continue Reading

References

Apr 3, 1992·Cell·G I EvanD C Hancock
Apr 18, 1997·The Journal of Biological Chemistry·G J ClarkC J Der
May 16, 2000·The Journal of Biological Chemistry·V A PolunovskyP B Bitterman
Jun 9, 2001·Methods in Cell Biology·M E McCurrach, S W Lowe
Jan 25, 2002·Genes, Chromosomes & Cancer·Sukvarsha MehraR S K Chaganti
Jun 28, 2002·Cancer Cell·Clemens A SchmittScott W Lowe
Jul 3, 2002·Nature Reviews. Cancer·Igor Vivanco, Charles L Sawyers
Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Andrew R TeeJohn Blenis
Jun 17, 2003·Proceedings of the National Academy of Sciences of the United States of America·Zirong LiBing Ren
Jul 19, 2003·Genes & Development·Ken InokiKun-Liang Guan
Mar 19, 2004·Nature·Hans-Guido WendelScott W Lowe
Mar 31, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Razelle KurzrockHagop M Kantarjian
Apr 20, 2004·Oncogene·Yaël MamaneNahum Sonenberg
Aug 18, 2004·Genes & Development·Nissim Hay, Nahum Sonenberg
Aug 18, 2004·Genes & Development·Qiaoran XiRobert J Schneider
Oct 7, 2004·Cell Cycle·Steven Le GouillKenneth C Anderson
Jul 20, 2005·Genes & Development·Brendan D ManningLewis C Cantley
Nov 10, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Andrew B LassmanEric C Holland
Apr 25, 2006·Biochemical and Biophysical Research Communications·Claudia BuergerVuk Stambolic
Oct 17, 2006·Oncogene·Y MamaneN Sonenberg
Nov 23, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anja HilliardYouhai H Chen
Jul 7, 2007·Cancer Cell·David A Guertin, David M Sabatini
Oct 5, 2007·The Journal of Investigative Dermatology·Magdalena KarbowniczekElizabeth P Henske
Oct 13, 2007·Science·Laura D WoodBert Vogelstein
Dec 7, 2007·Genes & Development·Hans-Guido WendelScott W Lowe

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Citations

Jan 27, 2009·Apoptosis : an International Journal on Programmed Cell Death·M Cecilia CainoMarcelo G Kazanietz
May 7, 2011·Targeted Oncology·Shin Ogita, Patricia Lorusso
Apr 16, 2011·Leukemia·L S SteelmanJ A McCubrey
Oct 18, 2011·Nature Chemical Biology·Shehab A IsmailAlfred Wittinghofer
Jun 7, 2011·Nature Genetics·Konstantinos J MavrakisHans-Guido Wendel
Mar 25, 2010·Nature Reviews. Cancer·Deborah SilveraRobert J Schneider
Oct 25, 2011·Nature Reviews. Cancer·Norbert BerndtSaïd M Sebti
Jan 6, 2010·The Journal of Biological Chemistry·Dongzhu MaYu Jiang
Aug 24, 2011·The Journal of Experimental Medicine·Jonathan H SchatzHans-Guido Wendel
Mar 27, 2009·Carcinogenesis·Daniel A TennantEyal Gottlieb
May 4, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Maria E BalasisSaïd M Sebti
Sep 30, 2010·Disease Models & Mechanisms·Elisa OricchioHans-Guido Wendel
Mar 3, 2009·PloS One·Kirsten H LimesandSteven M Anderson
Jun 3, 2011·The Oncologist·Anas Younes, Nousheen Samad
Dec 17, 2014·Molecular Biology International·Mehvish ShowkatKhurshid I Andrabi
Nov 20, 2014·Science Signaling·Viraj R SanghviHans-Guido Wendel
Aug 27, 2009·Expert Opinion on Therapeutic Targets·Francis Robert, Jerry Pelletier
Feb 26, 2016·Science·Konstantinos J MavrakisWilliam R Sellers
Aug 15, 2009·Expert Opinion on Investigational Drugs·Alberto M MartelliJames A McCubrey
Aug 4, 2015·International Journal of Cancer. Journal International Du Cancer·Marisol E ArmijoAriel F Castro
Feb 11, 2016·Seminars in Cell & Developmental Biology·Ellie Rad, Andrew R Tee
Jan 17, 2015·Molecular Carcinogenesis·Tania CamposAriel F Castro
Oct 15, 2010·The Journal of Investigative Dermatology·Heike NiessnerFriedegund Meier
Dec 29, 2015·Histochemistry and Cell Biology·Qi TianLev M Fedorov
Feb 9, 2011·Journal of Cellular Physiology·James A McCubreyAlberto M Martelli
Aug 9, 2011·Advances in Hematology·Pinelopi ArgyriouSotirios Papageorgiou
Dec 3, 2014·Biochimica Et Biophysica Acta·Kai XuWenyi Wei
Apr 14, 2016·Journal of Hematology & Oncology·Yanan GaoWeiping Yuan
Nov 1, 2011·Cell·Elisa OricchioHans-Guido Wendel
Aug 12, 2016·Surgical Neurology International·Naoki NittaKazuhiko Nozaki

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