title: CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death.
abstract: During hypoxia, gene expression is altered by various transcription factors. Insulin-like growth factor-II (IGF2) is known to be induced by hypoxia, which binds to IGF2 receptor IGF2R that acts like a G protein-coupled receptor, might cause pathological hypertrophy or activation of the mitochondria-mediated apoptosis pathway. Cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) is central to second messenger-regulated transcription and plays a critical role in the cardiomyocyte survival pathway. In this study, we found that IGF2R level was enhanced in H9c2 cardiomyoblasts exposed to hypoxia in a time-dependent manner but was down-regulated by CREB expression. The over-expression of CREB in H9c2 cardiomyoblasts suppressed the induction of hypoxia-induced IGF2R expression levels and reduced cell apoptosis. Gel shift assay results further indicated that CREB binds to the promoter sequence of IGF2R. With a luciferase assay method, we further observed that CREB represses IGF2R promoter activity. These results suggest that CREB plays an important role in the inhibition of IGF2R expression by binding to the IGF2R promoter and further suppresses H9c2 cardiomyoblast cell apoptosis induced by IGF2R signaling under hypoxic conditions.
authors.affiliation: Department of Emergency Medicine, China Medical University Hospital, Taichung 40402, Taiwan. ercwk@mail.cmuh.org.tw.
authors.forename: Wei-Kung
authors.initials: WK
authors.lastname: Chen
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan. wwkuo@mail.cmu.edu.tw.
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.affiliation: School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan. djh@csmu.edu.tw.
authors.forename: Dennis Jine-Yuan
authors.initials: DJ
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan. dadalidada0809@gmail.com.
authors.forename: Hsin-Nung
authors.initials: HN
authors.lastname: Chang
authors.affiliation: Division of Cardiology, China Medical University Hospital, Taichung 40402, Taiwan. paidoctor1@gmail.com.
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Pai
authors.affiliation: Department of Emergency Medicine, China Medical University Hospital, Taichung 40402, Taiwan. linalpra@hotmail.com.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan. linalpra@hotmail.com.|College of Medicine, China Medical University, Taichung 40402, Taiwan. linalpra@hotmail.com.
authors.forename: Kuan-Ho
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Cardiology Department, Taichung Armed Forces General Hospital. Taichung 41152, Taiwan. lung-fa@803.org.tw.|Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan. lung-fa@803.org.tw.
authors.forename: Lung-Fa
authors.initials: LF
authors.lastname: Pan
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan. tjho@mail.cmu.edu.tw.|Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin 651, Taiwan. tjho@mail.cmu.edu.tw.
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.affiliation: Department of Biotechnology, Bharathiar University, Coimbatore-641 046, India. padma.vijaya@gmail.com.
authors.forename: Vijaya Padma
authors.initials: VP
authors.lastname: Viswanadha
authors.affiliation: Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin 651, Taiwan. cyhuang@mail.cmu.edu.tw.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan. cyhuang@mail.cmu.edu.tw.|Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan. cyhuang@mail.cmu.edu.tw.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D017527:Receptor, IGF Type 2
keywords: CREB; IGF2R signaling; apoptosis; hypoxia