Abstract
Presenilin1 (PS1) is a component of the γ-secretase complex mutated in cases of Familial Alzheimer's disease (FAD). PS1 is synthesized as a 50 kDa peptide subsequently processed to two 29 and 20 kDa subunits that remain associated. Processing of PS1 is inhibited by several mutations detected in FAD patients. PS1 acts as negative modulator of β-catenin·Tcf-4 transcriptional activity. In this article we show that in murine embryonic fibroblasts (MEFs) the mechanisms of action of the processed and non-processed forms of PS1 on β-catenin·Tcf-4 transcription are different. Whereas non-processed PS1 inhibits β-catenin·Tcf-4 activity through a mechanism independent of γ-secretase and associated with the interaction of this protein with plakoglobin and Tcf-4, the effect of processed PS1 is prevented by γ-secretase inhibitors, and requires its interaction with E- or N-cadherin and the generation of cytosolic terminal fragments of these two cadherins, which in turn destabilize the β-catenin transcriptional cofactor CBP. Accordingly, the two forms of PS1 interact differently with E-cadherin or β-catenin and plakoglobin: whereas processed PS1 binds E-cadherin with high affinity and β-catenin or plakoglobin weakly, the non-processed form behaves inversely. Moreover, contrarily to processed PS1, that decreases the levels of c-fos RNA, non-processed PS1 inhibits the expression c-myc, a known target of β-catenin·Tcf-4, and does not block the activity of other transcriptional factors requiring CBP. These results indicate that prevention of PS1 processing in FAD affects the mechanism of repression of the transcriptional activity dependent on β-catenin.
Highlights
Presenilin 1 (PS1) encodes a ubiquitously expressed, eighttransmembrane protein involved in most cases of early-onset Familial Alzheimer’s disease (FAD) [1,2]
Failed processing of PS1 and reduced cleavage of substrates has been detected in FAD patients carrying PS1 mutations; these PS1 mutants are deficient in the processing of Notch and N-cadherin [4,14,15]
The inhibition of TOP activity by both forms of PS1 was differently regulated by the c-secretase inhibitor L685,458 [43]: whereas this compound did not affect the repression by npPS1, it totally prevented the effect of pPS1 (Figure 1B)
Summary
Presenilin 1 (PS1) encodes a ubiquitously expressed, eighttransmembrane protein involved in most cases of early-onset Familial Alzheimer’s disease (FAD) [1,2]. The resulting intracellular proteolytic products (CTF2 in the case of cadherins) contain the cytosolic domains of the substrate proteins. When released from the junction complex, b-catenin translocates to the nucleus, where it interacts with the Tcf-family of transcriptional factors and regulates the expression of a variety of genes involved in embryonic development and tumorigenesis [20,21]. The translocation of bcatenin to the nucleus is tightly controlled by the activity of a complex involved in b-catenin degradation. This complex includes the product of the tumor suppressor adenomatous polyposis gene, axin, and the Thr/Ser protein kinases, CKIa and glycogen synthase kinase 3b (GSK3b) [24]. Since interaction of plakoglobin with Tcf-4 precludes binding of Tcf-4 to DNA, plakoglobin works as a negative regulator of the b-catenin-Tcf-4 complex [25,26,27,28]
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