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CREB regulates the expression of PERK and IRE1a, and controls unfolded protein response under hypoxic conditions
Author(s) -
Nakayama Koh
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.647.9
Subject(s) - creb , unfolded protein response , transcription factor , activating transcription factor , microbiology and biotechnology , hypoxia (environmental) , atf4 , biology , chemistry , cancer research , genetics , endoplasmic reticulum , gene , oxygen , organic chemistry
Cells are frequently exposed to different stresses. Hypoxic condition induces ER stress, and activates unfolded protein response (UPR) to maintain homeostasis. Whereas Hypoxia‐inducible factor plays a major role in an adaptation to hypoxia, we previously identified that transcription factor CREB also has an important role in this process. To further understand the role of CREB in hypoxic response, CREB stable knock‐down cells (CREB‐KD) were established from breast cancer MDA‐MB231 cells and analyzed. CREB was found to be activated by ER stress, and the activation of CREB and UPR pathway occurred in a coordinated manner by various stimuli, including ER stress‐inducing chemicals, hypoxia and oxygen‐glucose deprivation (OGD). Depletion of CREB decreased the expression of PERK and IRE1a, two of the critical UPR signaling molecules. ChIP assay and promoter analysis indicated that CREB interacts with the promoter region of these molecules and regulate the expression of them. ER stress induced by hypoxia was found to be reduced in CREB‐KD cells, which led to less pulmonary metastasis in mice. Finally, OGD strongly activated UPR and induced cell death in control cells, whereas this activity was moderate in CREB‐KD cells, thus more resistant to cell death. Taken together, the study demonstrates a previously unknown role of CREB as a regulator of ER stress in cells, which is required for a proper response to the stressful conditions, such as hypoxia. Support or Funding Information Grant‐in‐Aid for Scientific Research C, and Grant‐in‐Aid for Scientific Research on Innovative Areas(KAKENHI).