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Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity

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...

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Autores principales: Raurell, Imma, Codina, Montserrat, Casagolda, David, del Valle, Beatriz, Baulida, Josep, de Herreros, Antonio García, Duñach, Mireia
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603589/
https://www.ncbi.nlm.nih.gov/pubmed/19114997
http://dx.doi.org/10.1371/journal.pone.0004080
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author Raurell, Imma
Codina, Montserrat
Casagolda, David
del Valle, Beatriz
Baulida, Josep
de Herreros, Antonio García
Duñach, Mireia
author_facet Raurell, Imma
Codina, Montserrat
Casagolda, David
del Valle, Beatriz
Baulida, Josep
de Herreros, Antonio García
Duñach, Mireia
author_sort Raurell, Imma
collection PubMed
description 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.
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spelling pubmed-26035892008-12-30 Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity Raurell, Imma Codina, Montserrat Casagolda, David del Valle, Beatriz Baulida, Josep de Herreros, Antonio García Duñach, Mireia PLoS One Research Article 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. Public Library of Science 2008-12-30 /pmc/articles/PMC2603589/ /pubmed/19114997 http://dx.doi.org/10.1371/journal.pone.0004080 Text en Raurell et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Raurell, Imma
Codina, Montserrat
Casagolda, David
del Valle, Beatriz
Baulida, Josep
de Herreros, Antonio García
Duñach, Mireia
Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity
title Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity
title_full Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity
title_fullStr Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity
title_full_unstemmed Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity
title_short Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity
title_sort gamma-secretase-dependent and -independent effects of presenilin1 on β-catenin·tcf-4 transcriptional activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603589/
https://www.ncbi.nlm.nih.gov/pubmed/19114997
http://dx.doi.org/10.1371/journal.pone.0004080
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