期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 415, 期 3, 页码 519-525出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2011.10.113
关键词
Sigma-1 receptor; Transcription factor; ATF4; Mental disorders; ER stress; Protective function
资金
- Ministry of Education, Culture, Sports, Science and Technology of japan
- Grants-in-Aid for Scientific Research [23591703] Funding Source: KAKEN
Sigma-1 receptors (Sig-1Rs) are the ER resident proteins. Sig-1Rs in the brain have been reported to be significantly reduced in patients with schizophrenia. The impediment of regulating Sig-1Rs expression levels increases the risk for schizophrenia. Thus elucidating the mechanism regulating Sig-1Rs expression might provide the strategy to prevent mental disorders. In this study, we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. Moreover, ATF4 directly bounds to the 5' flanking region of Sig-1R gene. The reporter activities using this region were enhanced in ER stress, or by ATF4 alone. The reporter activities with the pathogenic polymorphisms (GC-241-240TT, T-485A) were reduced. In addition, the processing of Caspase-4 was inhibited by Sig-1Rs. These results indicate that Sig-1Rs are transcriptionally upregulated via the PERK/eIF2 alpha/ATF4 pathway and ameliolate cell death signaling. This study is the first report identifying the transcription factor regulating Sig-1Rs expression. (C) 2011 Elsevier Inc. All rights reserved.
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