Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 469, Issue 2, Pages 243-250Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2015.11.113
Keywords
CREB; Unfolded protein response; Hypoxia; ER stress; PERK; IRE1 alpha
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Funding
- Takeda Science Foundation
- Japan Foundation for Applied Enzymology
- Kato Memorial Bioscience Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- JSPS KAKENHI [15K08260, 15H01396]
- Grants-in-Aid for Scientific Research [15H01396, 15K08260] Funding Source: KAKEN
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Living cells are frequently exposed to various stresses. Hypoxic conditions induce endoplasmic reticulum (ER) stress, and activate the unfolded protein response (UPR) to maintain homeostasis. We previously reported that CREB has an important role in the proper response to prolonged hypoxia. To further understand the role of CREB in the hypoxic response, CREB stable knock-down (CREB-KD) cells were established from breast cancer MDA-MB231 cells and analyzed. CREB was activated by ER stress, and activation of CREB and the UPR pathway occurred in a coordinated manner in response to different stimuli, including ER stress-inducing chemicals, prolonged hypoxia, and oxygen-glucose deprivation (OGD). Depletion of CREB decreased the expression of IRE1 alpha and PERK, two critical UPR signaling molecules. Promoter analysis and a chromatin immunoprecipitation assay indicated that CREB binds to the promoter region of these genes and regulates their expression. ER stress induced by hypoxia was reduced in CREB-KD cells, leading to reduced tumor metastasis to the lung. Finally, OGD strongly activated the UPR and induced cell death in control cells, whereas the UPR was moderately activated in CREB-KD cells, which were more resistant to cell death. This study demonstrates a new role for CREB as a regulator of ER stress, which is required to properly respond to stressful conditions, such as hypoxia. (C) 2015 Elsevier Inc. All rights reserved.
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