title: CREB is activated by ER stress and modulates the unfolded protein response by regulating the expression of IRE1α and PERK.
abstract: 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 IRE1α 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.
authors.affiliation: Oxygen Biology Laboratory, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kikuchi
authors.affiliation: Genome Laboratory, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Oxygen Biology Laboratory, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan. Electronic address: nakayama.mtt@mri.tmd.ac.jp.
authors.forename: Koh
authors.initials: K
authors.lastname: Nakayama
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000737:chemistry / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases
keywords: CREB; ER stress; Hypoxia; IRE1α; PERK; Unfolded protein response