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Molecular and Cellular Biology, September 2004, p. 7469-7482, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7469-7482.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress

Jaime D. Blais,1,2 Vasilisa Filipenko,2 Meixia Bi,3 Heather P. Harding,4 David Ron,4 Costas Koumenis,3 Bradly G. Wouters,5 and John C. Bell1*

Ottawa Regional Cancer Center, Ontario,1 Department of Biochemistry, University of Ottawa, Ottawa, Canada,2 Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina,3 Skirball Institute, New York University School of Medicine, New York, New York,4 Department of Radiotherapy, University of Maastricht, Maastricht, The Netherlands5

Received 5 February 2004/ Returned for modification 8 March 2004/ Accepted 9 June 2004

Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2{alpha} (eIF2{alpha}) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2{alpha} at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2{alpha} was able to attenuate the phosphorylation of eIF2{alpha} and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2{alpha}-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.

* Corresponding author. Mailing address: ORCC, 503 Smyth Rd., 3rd Fl., Ottawa, Ontario K1H 1C4, Canada. Phone: (613) 737-7700, ext. 6893. Fax: (613) 247-3524. E-mail: jbell{at}ohri.ca.

Molecular and Cellular Biology, September 2004, p. 7469-7482, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7469-7482.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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