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Transcriptional Regulation of PEN-2, a Key Component of the -Secretase Complex, by CREB

Ruishan Wang,^1,2, Yun-wu Zhang,^3, Ping Sun,³ Runzhong Liu,² Xian Zhang,^2,3 Xue Zhang,³ Kun Xia,¹ Jiahui Xia,¹ Huaxi Xu,^1,2,3* and Zhuohua Zhang^1,3*

National Laboratory of Medical Genetics of China, Xiang-Ya Hospital, Central South University, 410078 Changsha, China,¹ Laboratory of Molecular and Cellular Neuroscience, School of Life Sciences, Xiamen University, Xiamen 361005, China,² Center for Neuroscience and Aging, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037³

Received 14 September 2005/ Returned for modification 7 October 2005/ Accepted 28 November 2005

Gamma-secretase, which is responsible for the intramembranous cleavage of Alzheimer's ß-amyloid precursor protein (APP), the signaling receptor Notch, and many other substrates, is a multiprotein complex consisting of at least four components: presenilin (PS), nicastrin, APH-1, and PEN-2. Despite the fact that PEN-2 is known to mediate endoproteolytic cleavage of full-length PS and APH-1 and nicastrin are required for maintaining the stability of the complex, the detailed physiological function of each component remain elusive. Unlike that of PS, the transcriptional regulation of PEN-2, APH-1, and nicastrin has not been investigated. Here, we characterized the upstream regions of the human PEN-2 gene and identified a 238-bp fragment located 353 bp upstream of the translational start codon as the key region necessary for the promoter activity. Further analysis revealed a CREB binding site located in the 238-bp region that is essential for the transcriptional activity of the PEN-2 promoter. Mutation of the CREB site abolished the transcriptional activity of the PEN-2 promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed the binding of CREB to the PEN-2 promoter region both in vitro and in vivo. Activation of the CREB transcriptional factor by forskolin dramatically promoted the expression of PEN-2 mRNA and protein, whereas the other components of the -secretase complex remained unaffected. Forskolin treatment slightly increases the secretion of soluble APP and Aß without affecting Notch cleavage. These results demonstrate that expression of PEN-2 is regulated by CREB and suggest that the specific control of PEN-2 expression may imply additional physiological functions uniquely assigned to PEN-2.

These authors contributed equally to this work.

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