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Molecular and Cellular Biology, February 2006, p. 1347-1354, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1347-1354.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Ruishan Wang,1,2,{dagger} Yun-wu Zhang,3,{dagger} 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 Zhang1,3*

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 {gamma}-secretase complex remained unaffected. Forskolin treatment slightly increases the secretion of soluble APP{alpha} 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.

* Corresponding author. Mailing address for Zhuohua Zhang: National Laboratory of Medical Genetics of China, Xiang-Ya Hospital, Central South University, 410078 Changsha, Hunan, China. Phone: 86-731-4805358. Fax: 86-731-4478152. E-mail: benzz{at}burnham.org. Mailing address for Huaxi Xu: Laboratory of Molecular and Cellular Neuroscience, School of Life Sciences, Xiamen University, Xiamen 361005, China. Phone: 86-592-2188568. Fax: 86-592-2188528. E-mail: xuh{at}burnham.org.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, February 2006, p. 1347-1354, Vol. 26, No. 4
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.4.1347-1354.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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