Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity.
Presenilin1 (PS1) is a component of the gamma-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 detecte...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2603589?pdf=render |
| _version_ | 1818557854054875136 |
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| author | Imma Raurell Montserrat Codina David Casagolda Beatriz Del Valle Josep Baulida Antonio García de Herreros Mireia Duñach |
| author_facet | Imma Raurell Montserrat Codina David Casagolda Beatriz Del Valle Josep Baulida Antonio García de Herreros Mireia Duñach |
| author_sort | Imma Raurell |
| collection | DOAJ |
| description | Presenilin1 (PS1) is a component of the gamma-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 beta-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 beta-catenin.Tcf-4 transcription are different. Whereas non-processed PS1 inhibits beta-catenin.Tcf-4 activity through a mechanism independent of gamma-secretase and associated with the interaction of this protein with plakoglobin and Tcf-4, the effect of processed PS1 is prevented by gamma-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 beta-catenin transcriptional cofactor CBP. Accordingly, the two forms of PS1 interact differently with E-cadherin or beta-catenin and plakoglobin: whereas processed PS1 binds E-cadherin with high affinity and beta-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 beta-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 beta-catenin. |
| first_indexed | 2024-12-14T00:05:08Z |
| format | Article |
| id | doaj.art-d65bc44a44fa44b48d9c4b7f08f993f0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T00:05:08Z |
| publishDate | 2008-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d65bc44a44fa44b48d9c4b7f08f993f02022-12-21T23:26:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-01-01312e408010.1371/journal.pone.0004080Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity.Imma RaurellMontserrat CodinaDavid CasagoldaBeatriz Del ValleJosep BaulidaAntonio García de HerrerosMireia DuñachPresenilin1 (PS1) is a component of the gamma-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 beta-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 beta-catenin.Tcf-4 transcription are different. Whereas non-processed PS1 inhibits beta-catenin.Tcf-4 activity through a mechanism independent of gamma-secretase and associated with the interaction of this protein with plakoglobin and Tcf-4, the effect of processed PS1 is prevented by gamma-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 beta-catenin transcriptional cofactor CBP. Accordingly, the two forms of PS1 interact differently with E-cadherin or beta-catenin and plakoglobin: whereas processed PS1 binds E-cadherin with high affinity and beta-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 beta-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 beta-catenin.http://europepmc.org/articles/PMC2603589?pdf=render |
| spellingShingle | Imma Raurell Montserrat Codina David Casagolda Beatriz Del Valle Josep Baulida Antonio García de Herreros Mireia Duñach Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity. PLoS ONE |
| title | Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity. |
| title_full | Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity. |
| title_fullStr | Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity. |
| title_full_unstemmed | Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity. |
| title_short | Gamma-secretase-dependent and -independent effects of presenilin1 on beta-catenin.Tcf-4 transcriptional activity. |
| title_sort | gamma secretase dependent and independent effects of presenilin1 on beta catenin tcf 4 transcriptional activity |
| url | http://europepmc.org/articles/PMC2603589?pdf=render |
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