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Int. J. Mol. Sci. 2015, 16(11), 27921-27930; doi:10.3390/ijms161126067

CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death

1
Department of Emergency Medicine, China Medical University Hospital, Taichung 40402, Taiwan
2
Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan
3
School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan
4
Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan
5
Division of Cardiology, China Medical University Hospital, Taichung 40402, Taiwan
6
College of Medicine, China Medical University, Taichung 40402, Taiwan
7
Cardiology Department, Taichung Armed Forces General Hospital. Taichung 41152, Taiwan
8
Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan
9
School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
10
Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin 651, Taiwan
11
Department of Biotechnology, Bharathiar University, Coimbatore-641 046, India
12
Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
13
Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: H. W. M. Niessen
Received: 14 September 2015 / Accepted: 23 October 2015 / Published: 24 November 2015
(This article belongs to the Special Issue Improvement of Cardiac Function in Heart Failure)
View Full-Text   |   Download PDF [2379 KB, uploaded 24 November 2015]   |  

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. View Full-Text
Keywords: CREB; hypoxia; apoptosis; IGF2R signaling CREB; hypoxia; apoptosis; IGF2R signaling
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Chen, W.-K.; Kuo, W.-W.; Hsieh, D.J.-Y.; Chang, H.-N.; Pai, P.-Y.; Lin, K.-H.; Pan, L.-F.; Ho, T.-J.; Viswanadha, V.P.; Huang, C.-Y. CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death. Int. J. Mol. Sci. 2015, 16, 27921-27930.

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