Ngb (neuroglobin) has been identified as a novel endogenous neuroprotectant. However, little is known about the regulatory mechanisms of Ngb expression, especially under conditions of hypoxia. In the present study, we located the core proximal promoter of the mouse Ngb gene to a 554 bp segment, which harbours putative conserved NF-κB (nuclear factor κB)- and Egr1 (early growth-response factor 1) -binding sites. Overexpression and knockdown of transcription factors p65, p50, Egr1 or Sp1 (specificity protein 1) increased and decreased Ngb expression respectively. Experimental assessments with transfections of mutational Ngb gene promoter constructs, as well as EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) assays, demonstrated that NF-κB family members (p65, p50 and cRel), Egr1 and Sp1 bound in vitro and in vivo to the proximal promoter region of the Ngb gene. Moreover, a κB3 site was found as a pivotal cis-element responsible for hypoxia-induced Ngb promoter activity. NF-κB (p65) and Sp1 were also responsible for hypoxia-induced up-regulation of Ngb expression. Although there are no conserved HREs (hypoxia-response elements) in the promoter of the mouse Ngb gene, the results of the present study suggest that HIF-1α (hypoxia-inducible factor-1α) is also involved in hypoxia-induced Ngb up-regulation. In conclusion, we have identified that NF-κB, Egr1 and Sp1 played important roles in the regulation of basal Ngb expression via specific interactions with the mouse Ngb promoter. NF-κB, Sp1 and HIF-1α contributed to the up-regulation of mouse Ngb gene expression under hypoxic conditions.
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Research Article|
March 14 2012
Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression
Ning Liu;
Ning Liu
*Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China, College of Life Science, Hunan Normal University, Changsha 410081, China
†Departments of Neurology and Radiology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, U.S.A.
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Zhanyang Yu;
Zhanyang Yu
†Departments of Neurology and Radiology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, U.S.A.
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Shuanglin Xiang;
Shuanglin Xiang
*Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China, College of Life Science, Hunan Normal University, Changsha 410081, China
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Song Zhao;
Song Zhao
†Departments of Neurology and Radiology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, U.S.A.
‡Department of Orthopedics, Spine Division, The First Hospital of Jilin University, Changchun, Jilin, China
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Anna Tjärnlund-Wolf;
Anna Tjärnlund-Wolf
†Departments of Neurology and Radiology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, U.S.A.
§Section for Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
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Changhong Xing;
Changhong Xing
†Departments of Neurology and Radiology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, U.S.A.
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Jian Zhang;
Jian Zhang
1
*Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China, College of Life Science, Hunan Normal University, Changsha 410081, China
1Correspondence may be addressed to either of these authors (email zhangjian@hunnu.edu.cn or wangxi@helix.mgh.harvard.edu).
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Xiaoying Wang
Xiaoying Wang
1
†Departments of Neurology and Radiology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, U.S.A.
1Correspondence may be addressed to either of these authors (email zhangjian@hunnu.edu.cn or wangxi@helix.mgh.harvard.edu).
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Publisher: Portland Press Ltd
Received:
October 18 2011
Revision Received:
December 15 2011
Accepted:
January 13 2012
Accepted Manuscript online:
January 13 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (1): 153–164.
Article history
Received:
October 18 2011
Revision Received:
December 15 2011
Accepted:
January 13 2012
Accepted Manuscript online:
January 13 2012
Citation
Ning Liu, Zhanyang Yu, Shuanglin Xiang, Song Zhao, Anna Tjärnlund-Wolf, Changhong Xing, Jian Zhang, Xiaoying Wang; Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression. Biochem J 1 April 2012; 443 (1): 153–164. doi: https://doi.org/10.1042/BJ20111856
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