Transcriptional regulation of the presenilin-1 gene controls gamma-secretase activity

10.2741/e61 ◽  
2010 ◽  
Vol E2 (1) ◽  
pp. 22-35 ◽  
Author(s):  
Hriday K Das
2004 ◽  
Vol 25 ◽  
pp. S559
Author(s):  
Neil S. Shachter ◽  
Yanzhu Liu ◽  
Lin Yang ◽  
Karin Conde-Knape ◽  
Dirk Beher ◽  
...  

2000 ◽  
Vol 97 (11) ◽  
pp. 6138-6143 ◽  
Author(s):  
Y.-M. Li ◽  
M.-T. Lai ◽  
M. Xu ◽  
Q. Huang ◽  
J. DiMuzio-Mower ◽  
...  

2006 ◽  
Vol 26 (4) ◽  
pp. 1347-1354 ◽  
Author(s):  
Ruishan Wang ◽  
Yun-wu Zhang ◽  
Ping Sun ◽  
Runzhong Liu ◽  
Xian Zhang ◽  
...  

ABSTRACT Gamma-secretase, which is responsible for the intramembranous cleavage of Alzheimer's β-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 γ-secretase complex remained unaffected. Forskolin treatment slightly increases the secretion of soluble APPα and Aβ 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.


2015 ◽  
Vol 133 (3) ◽  
pp. 409-421 ◽  
Author(s):  
Alexandre Matz ◽  
Blanka Halamoda-Kenzaoui ◽  
Romain Hamelin ◽  
Sebastien Mosser ◽  
Jean-René Alattia ◽  
...  

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