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dc.contributor.authorWang, Ruishan( National Laboratory of Medical Genetics of China, Xiang-Ya Hospital, Central South University, Changsha)
dc.contributor.authorZhang, Yun-Wu
dc.contributor.authorZhang, Xian(Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, California, USA )
dc.contributor.authorLiu, Runzhong
dc.contributor.author刘润忠
dc.contributor.authorZhang, Xue(Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, California, USA )
dc.contributor.authorHong, Shuigen
dc.contributor.author洪水根
dc.contributor.authorXia, Kun( National Laboratory of Medical Genetics of China, Xiang-Ya Hospital, Central South University, Changsha)
dc.contributor.authorXia, Jiahui( National Laboratory of Medical Genetics of China, Xiang-Ya Hospital, Central South University, Changsha)
dc.contributor.authorZhang, Zhuohua(Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, California, USA )
dc.contributor.authorXu, Huaxi(Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, California, USA )
dc.date.accessioned2011-09-02T00:51:18Z
dc.date.available2011-09-02T00:51:18Z
dc.date.issued2006
dc.identifier.citationThe FASEB Journal. 2006;20:1275-1277zh_CN
dc.identifier.issn0892-6638
dc.identifier.urihttp://dx.doi.org/doi:10.1096/fj.06-5839fje
dc.identifier.urihttps://dspace.xmu.edu.cn/handle/2288/10723
dc.description.abstractThe proteolytic cleavage of Alzheimer beta-amyloid precursor protein (APP) and signaling receptor Notch is mediated by the PS/gamma-secretase complex, which consists of presenilins, nicastrin, APH-1, and PEN-2. Although the four components are known to coordinately regulate each other at the protein level, information regarding their transcription regulation is scarce. Here we characterized the 5'-flanking region of the human APH-1A gene and identified a 271-bp fragment containing the transcription initiation site for the promoter activity. Sequence analysis, mutagenesis, and gel shift studies revealed a binding of AP4 and HIF-1 to the promoter, which affects the promoter activity. Activation of HIF-1 by short- term NiCl2 treatments ( a condition of chemical hypoxia) dramatically increased APH-1A mRNA and protein expression, accompanied by increased secretion of A beta and decreased APP CTFs formation, indicative of an increase in gamma-secretase activity. NiCl2 treatments had little effect on APP and the other three components of the gamma-secretase complex. The cellular concentration of Notch intracellular domain (NICD) was also increased by the hypoxic treatment. Our results demonstrate that APH-1A expression and the gamma-secretase mediated A beta and Notch NICD generation are regulated by HIF-1, and the specific control of APH-1A expression may imply physiological functions uniquely assigned to APH-1A. Wang, R., Zhang, Y-w., Zhang, X., Liu, R., Zhang, X., Hong, S., Xia, K., Xia, J., Zhang, Z., Xu, H. Transcriptional regulation of APH-1A and increased gamma-secretase cleavage of APP and Notch by HIF-1 and hypoxia.zh_CN
dc.language.isoenzh_CN
dc.publisherFEDERATION AMER SOC EXP BIOLzh_CN
dc.subjectAlzheimer's diseasezh_CN
dc.subjectAP4zh_CN
dc.subjectpromoterzh_CN
dc.titleTranscriptional regulation of APH-1A and increased gamma-secretase cleavage of APP and Notch by HIF-1 and hypoxiazh_CN
dc.typeArticlezh_CN


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