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| ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth |
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| Author(s): Bi MX, Naczki C, Koritzinsky M, Fels D, Blais J, Hu NP, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C |
| Source: EMBO JOURNAL Volume: 24 Issue: 19 Pages: 3470-3481 Published: OCT 5 2005 |
| Times Cited: 116 References: 43 |
| Abstract: Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we demonstrate that cells cultured under hypoxic/ anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum ( ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2 alpha or by a dominant-negative PERK impairs cell survival under extreme hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of the ISR targets ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities. |
| Document Type: Article |
| Language: English |
| Reprint Address: Koumenis, C (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Radiat Oncol, NRC, Room 411,Med Ctr Blvd, Winston Salem, NC 27157 USA |
Addresses:
1. Wake Forest Univ, Bowman Gray Sch Med, Dept Radiat Oncol, NRC, Winston Salem, NC 27157 USA
2. Univ Maastricht, GROW Res Inst, Dept Radiat Oncol, Maastricht, Netherlands
3. Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Winston Salem, NC USA
4. Ottawa Reg Canc Ctr, Ottawa, ON K1Y 4K7 Canada
5. NYU, Sch Med, Skirball Inst Biomol Med, New York, NY USA
6. Univ N Carolina, Sch Med, Dept Radiat Oncol, Chapel Hill, NC 27599 USA
7. Univ Michigan, Med Ctr, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
8. Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA
9. Wake Forest Univ, Bowman Gray Sch Med, Dept Neurosurg, Winston Salem, NC USA |
| Publisher: NATURE PUBLISHING GROUP, 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA |
| Subject Category: Biochemistry & Molecular Biology; Cell Biology |
| IDS Number: 973VX |
| ISSN: 0261-4189 |
| DOI: 10.1038/sj.emboj.7600777 |
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