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| Activating transcription factor 4 is translationally regulated by hypoxic stress |
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| Author(s): Blais JD, Filipenko V, Bi MX, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC |
| Source: MOLECULAR AND CELLULAR BIOLOGY Volume: 24 Issue: 17 Pages: 7469-7482 Published: SEP 2004 |
| Times Cited: 130 References: 64 |
| Abstract: Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2alpha (eIF2alpha) 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 eIF2alpha 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 eIF2alpha was able to attenuate the phosphorylation of eIF2alpha 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 eIF2alpha-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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Bell, JC (reprint author), ORCC, 503 Smyth Rd,3rd Fl, Ottawa, ON K1H 1C4 Canada |
Addresses:
1. ORCC, Ottawa, ON K1H 1C4 Canada
2. Univ Ottawa, Dept Biochem, Ottawa, ON K1N 6N5 Canada
3. Wake Forest Univ, Sch Med, Dept Radiat Oncol, Winston Salem, NC 27109 USA
4. NYU, Sch Med, Skirball Inst, New York, NY USA
5. Univ Maastricht, Dept Radiotherapy, Maastricht, Netherlands |
| Publisher: AMER SOC MICROBIOLOGY, 1752 N ST NW, WASHINGTON, DC 20036-2904 USA |
| Subject Category: Biochemistry & Molecular Biology; Cell Biology |
| IDS Number: 848CD |
| ISSN: 0270-7306 |
| DOI: 10.1128/MCB.24.17.7469-7482.2004 |
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