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Molecular and Cellular Biology, June 2008, p. 3729-3741, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.02284-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hypoxic Inhibition of Nonsense-Mediated RNA Decay Regulates Gene Expression and the Integrated Stress Response {triangledown} ,{dagger}

Lawrence B. Gardner*

New York University School of Medicine, Department of Medicine, Division of Hematology, Department of Pharmacology, NYU Cancer Institute, New York City, New York 10016

Received 26 December 2007/ Returned for modification 20 February 2008/ Accepted 14 March 2008

Nonsense-mediated RNA decay (NMD) rapidly degrades both mutated mRNAs and nonmutated cellular mRNAs in what is thought to be a constitutive fashion. Here we demonstrate that NMD is inhibited in hypoxic cells and that this inhibition is dependent on phosphorylation of the {alpha} subunit of eukaryotic initiation factor 2 (eIF2{alpha}). eIF2{alpha} phosphorylation is known to promote translational and transcriptional up-regulation of genes important for the cellular response to stress. We show that the mRNAs of several of these stress-induced genes are NMD targets and that the repression of NMD stabilizes these mRNAs, thus demonstrating that the inhibition of NMD augments the cellular stress response. Furthermore, hypoxia-induced formation of cytoplasmic stress granules is also dependent on eIF2{alpha} phosphorylation, and components of the NMD pathway are relocalized to these granules in hypoxic cells, providing a potential mechanism for the hypoxic inhibition of NMD. Our demonstration that NMD is inhibited in hypoxic cells reveals that the regulation of NMD can dynamically alter gene expression and also establishes a novel mechanism for hypoxic gene regulation.

* Mailing address: Tisch 401, 550 1st Avenue, New York, NY 10016. Phone: (212) 263-8038. Fax: (212) 263-8444. E-mail: lawrence.gardner{at}med.nyu.edu

{triangledown} Published ahead of print on 24 March 2008.

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

Molecular and Cellular Biology, June 2008, p. 3729-3741, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.02284-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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