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Transcriptional regulation of APH-1A and increased -secretase cleavage of APP and Notch by HIF-1 and hypoxia

Ruishan Wang^*,,1, Yun-wu Zhang^,1, Xian Zhang^*,, Runzhong Liu^*, Xue Zhang, Shuigen Hong^*, Kun Xia, Jiahui Xia, Zhuohua Zhang^,,2 and Huaxi Xu^*,,,2

^* Laboratory of Molecular and Cellular Neuroscience, School of Life Sciences, and Institute for Biomedical Research, Xiamen University, Xiamen, China;

National Laboratory of Medical Genetics of China, Xiang-Ya Hospital, Central South University, Changsha, China; and

Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, California, USA

²Correspondence: Z. Z., National Laboratory of Medical Genetics of China, Xiang-Ya Hospital, Central South University, Changsha 410078, Hunan, China. E-mail: benzz@burnham.org; and H. X., Laboratory of Molecular and Cellular Neuroscience, School of Life Sciences, Xiamen University, Xiamen 361005, China. E-mail: xuh{at}burnham.org

ABSTRACT

The proteolytic cleavage of Alzheimer ß-amyloid precursor protein (APP) and signaling receptor Notch is mediated by the PS/-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 Aß and decreased APP CTFs formation, indicative of an increase in -secretase activity. NiCl₂ treatments had little effect on APP and the other three components of the -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 -secretase mediated Aß 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 -secretase cleavage of APP and Notch by HIF-1 and hypoxia.

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