Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells.

Molecular and Cellular Biology
Eileen ConnollyRobert J Schneider

Abstract

Hypoxia is a state of low oxygen availability that limits tumor growth. The mechanism of protein synthesis inhibition by hypoxia and its circumvention by transformation are not well understood. Hypoxic breast epithelial cells are shown to downregulate protein synthesis by inhibition of the kinase mTOR, which suppresses mRNA translation through a novel mechanism mitigated in transformed cells: disruption of proteasome-targeted degradation of eukaryotic elongation factor 2 (eEF2) kinase and activation of the regulatory protein 4E-BP1. In transformed breast epithelial cells under hypoxia, the mTOR and S6 kinases are constitutively activated and the mTOR negative regulator tuberous sclerosis complex 2 (TSC2) protein fails to function. Gene silencing of 4E-BP1 and eEF2 kinase or TSC2 confers resistance to hypoxia inhibition of protein synthesis in immortalized breast epithelial cells. Breast cancer cells therefore acquire resistance to hypoxia by uncoupling oxygen-responsive signaling pathways from mTOR function, eliminating inhibition of protein synthesis mediated by 4E-BP1 and eEF2.

References

Sep 3, 1996·Proceedings of the National Academy of Sciences of the United States of America·P W HochachkaS C Land
Apr 27, 1999·The International Journal of Biochemistry & Cell Biology·A E Willis
Jan 20, 2000·International Journal of Oncology·D B ZimonjicN C Popescu
May 24, 2000·Proceedings of the National Academy of Sciences of the United States of America·T CarsilloE P Henske
Jun 29, 2000·Annual Review of Biochemistry·A C GingrasN Sonenberg
Feb 22, 2001·Journal of the National Cancer Institute·M Höckel, P Vaupel
Jun 21, 2001·Proceedings of the National Academy of Sciences of the United States of America·T V PestovaC U Hellen
Aug 18, 2001·Journal of Applied Physiology·W W Winder
Nov 3, 2001·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·P W Hochachka, P L Lutz
Mar 9, 2002·The Journal of Biological Chemistry·Thomas H ReynoldsJohn C Lawrence
Nov 9, 2002·European Journal of Biochemistry·Gareth J Browne, Christopher G Proud
Mar 13, 2003·Breast Cancer Research : BCR·Sarah E BurdallValerie Speirs
Jun 5, 2003·The Journal of Biological Chemistry·Andrew M ArshamM Celeste Simon
Sep 6, 2003·Cancer Cell·James B BrugarolasWilliam G Kaelin
Apr 10, 2004·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Bradly G WoutersCostas Koumenis
Jun 16, 2004·Cancer Metastasis Reviews·Quynh-Thu LeAmato J Giaccia
Jul 16, 2004·Cancer Biology & Therapy·Liping Liu, M Celeste Simon
Jul 29, 2004·DNA Repair·Christopher G Proud
Aug 18, 2004·Genes & Development·Nissim Hay, Nahum Sonenberg
Aug 18, 2004·Molecular and Cellular Biology·Jaime D BlaisJohn C Bell
Dec 30, 2004·Nature Genetics·Ken InokiKun-Liang Guan
Jan 6, 2005·The Journal of Biological Chemistry·Michael N CorradettiKun-Liang Guan
May 19, 2005·The Journal of Biological Chemistry·Gary G Chiang, Robert T Abraham
May 21, 2005·The Journal of Biological Chemistry·Marina K Holz, John Blenis
Jul 1, 2005·Molecular and Cellular Biology·Avi SoferLeif W Ellisen
Feb 18, 2006·Molecular Cell·Liping LiuM Celeste Simon

❮ Previous
Next ❯

Citations

Jul 25, 2007·Cancer Metastasis Reviews·Bryan C Barnhart, M Celeste Simon
Jun 1, 2011·Cancer Microenvironment : Official Journal of the International Cancer Microenvironment Society·Kai BartkowiakKlaus Pantel
Oct 11, 2008·Nature Reviews. Cancer·Bradly G Wouters, Marianne Koritzinsky
Mar 25, 2010·Nature Reviews. Cancer·Deborah SilveraRobert J Schneider
Dec 29, 2010·Proceedings of the National Academy of Sciences of the United States of America·Zanna BeharryAndrew S Kraft
Aug 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Olga V LeontievaMikhail V Blagosklonny
Sep 5, 2008·The Journal of Biological Chemistry·Liping LiuM Celeste Simon
Sep 1, 2007·Antioxidants & Redox Signaling·Ronald C Wek, Douglas R Cavener
Aug 30, 2008·Journal of the National Cancer Institute·Daniela TrisciuoglioGiovanni Melillo
Mar 15, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mitsuteru NatsuizakaHiroshi Nakagawa
Apr 27, 2010·Eukaryotic Cell·César M Camilo, Suely L Gomes
Aug 26, 2009·Molecular and Cellular Biology·Steve BraunsteinRobert J Schneider
Oct 31, 2007·Molecular and Cellular Biology·Stefanie GalbánMyriam Gorospe
Sep 14, 2007·Annual Review of Physiology·M Celeste SimonRegina M Young
Feb 25, 2010·Molecular Cancer Research : MCR·Lawrence B Gardner
Oct 22, 2009·Cancer Prevention Research·Laurie A DavidsonRobert S Chapkin
Feb 22, 2013·The Journal of Clinical Investigation·Zhen ChenJohn Y-J Shyy
Jun 1, 2012·Future Oncology·Katherine S Bridge, Tyson V Sharp
May 24, 2014·Advances in Biological Regulation·Justin W KenneyChristopher G Proud
Jul 30, 2014·Cellular Oncology (Dordrecht)·Jee-Young ParkWon-Ki Baek
Oct 22, 2013·Biochimica Et Biophysica Acta·Anja RosenowJohan Renes
Nov 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Michelle BaduraRobert J Schneider
Feb 9, 2016·Cell Reports·J J David HoStephen Lee
Apr 23, 2008·The Journal of Cell Biology·Francisco Ramírez-ValleRobert J Schneider
Sep 17, 2014·Biotechnic & Histochemistry : Official Publication of the Biological Stain Commission·E T UluerM Sancı
Feb 24, 2016·Bulletin of Experimental Biology and Medicine·D V SorokinM A Krasil'nikov
Dec 30, 2015·Trends in Pharmacological Sciences·Biplab Dasgupta, Rishi Raj Chhipa
Oct 17, 2008·Comparative Biochemistry and Physiology. Part D, Genomics & Proteomics·Bryce A MendelsohnJonathan D Gitlin
May 29, 2007·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Marianne KoritzinskyBradly G Wouters
Jan 21, 2009·Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society·Chandan K Sen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Breast Tumorigenesis

Breast tumorigenesis involves the production or formation of tumor(s) in breast tissue. Discover the latest research on breast tumorigenesis here.