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Molecular and Cellular Biology, May 2006, p. 3955-3965, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3955-3965.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells{dagger}

Eileen Connolly,1,{ddagger} Steve Braunstein,1,{ddagger} Silvia Formenti,2 and Robert J. Schneider1*

Department of Microbiology,1 Department of Radiation Oncology, New York University School of Medicine, New York, New York 100162

Received 7 February 2006/ Returned for modification 28 February 2006/ Accepted 3 March 2006

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.

* Corresponding author. Mailing address: Department of Microbiology, New York University School of Medicine, New York, NY 10016. Phone: (212) 263-6006. Fax: (212) 263-8276. E-mail: schner01{at}med.nyu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} E.C. and S.B. contributed equally to this work.

Molecular and Cellular Biology, May 2006, p. 3955-3965, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3955-3965.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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