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Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity

BACKGROUND: Processing by γ-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes....

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Detalles Bibliográficos
Autores principales: Magold, Alexandra I., Cacquevel, Matthias, Fraering, Patrick C.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739295/
https://www.ncbi.nlm.nih.gov/pubmed/19763259
http://dx.doi.org/10.1371/journal.pone.0006952
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author Magold, Alexandra I.
Cacquevel, Matthias
Fraering, Patrick C.
author_facet Magold, Alexandra I.
Cacquevel, Matthias
Fraering, Patrick C.
author_sort Magold, Alexandra I.
collection PubMed
description BACKGROUND: Processing by γ-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes. Because the list of γ-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimer's disease therapeutic target, the mapping of γ-secretase activity susceptible gene transcription is important for sharpening our view of specific affected genes, molecular functions and biological pathways. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes and molecular functions transcriptionally affected by γ-secretase activity, the cellular transcriptomes of Chinese hamster ovary (CHO) cells with enhanced and inhibited γ-secretase activity were analyzed and compared by cDNA microarray. The functional clustering by FatiGO of the 1,981 identified genes revealed over- and under-represented groups with multiple activities and functions. Single genes with the most pronounced transcriptional susceptibility to γ-secretase activity were evaluated by real-time PCR. Among the 21 validated genes, the strikingly decreased transcription of PTPRG and AMN1 and increased transcription of UPP1 potentially support data on cell cycle disturbances relevant to cancer, stem cell and neurodegenerative diseases' research. The mapping of interactions of proteins encoded by the validated genes exclusively relied on evidence-based data and revealed broad effects on Wnt pathway members, including WNT3A and DVL3. Intriguingly, the transcription of TERA, a gene of unknown function, is affected by γ-secretase activity and was significantly altered in the analyzed human Alzheimer's disease brain cortices. CONCLUSIONS/SIGNIFICANCE: Investigating the effects of γ-secretase activity on gene transcription has revealed several affected clusters of molecular functions and, more specifically, 21 genes that hold significant potential for a better understanding of the biology of γ-secretase and its roles in cancer and Alzheimer's disease pathology.
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spelling pubmed-27392952009-09-18 Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity Magold, Alexandra I. Cacquevel, Matthias Fraering, Patrick C. PLoS One Research Article BACKGROUND: Processing by γ-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes. Because the list of γ-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimer's disease therapeutic target, the mapping of γ-secretase activity susceptible gene transcription is important for sharpening our view of specific affected genes, molecular functions and biological pathways. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes and molecular functions transcriptionally affected by γ-secretase activity, the cellular transcriptomes of Chinese hamster ovary (CHO) cells with enhanced and inhibited γ-secretase activity were analyzed and compared by cDNA microarray. The functional clustering by FatiGO of the 1,981 identified genes revealed over- and under-represented groups with multiple activities and functions. Single genes with the most pronounced transcriptional susceptibility to γ-secretase activity were evaluated by real-time PCR. Among the 21 validated genes, the strikingly decreased transcription of PTPRG and AMN1 and increased transcription of UPP1 potentially support data on cell cycle disturbances relevant to cancer, stem cell and neurodegenerative diseases' research. The mapping of interactions of proteins encoded by the validated genes exclusively relied on evidence-based data and revealed broad effects on Wnt pathway members, including WNT3A and DVL3. Intriguingly, the transcription of TERA, a gene of unknown function, is affected by γ-secretase activity and was significantly altered in the analyzed human Alzheimer's disease brain cortices. CONCLUSIONS/SIGNIFICANCE: Investigating the effects of γ-secretase activity on gene transcription has revealed several affected clusters of molecular functions and, more specifically, 21 genes that hold significant potential for a better understanding of the biology of γ-secretase and its roles in cancer and Alzheimer's disease pathology. Public Library of Science 2009-09-18 /pmc/articles/PMC2739295/ /pubmed/19763259 http://dx.doi.org/10.1371/journal.pone.0006952 Text en Magold 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
Magold, Alexandra I.
Cacquevel, Matthias
Fraering, Patrick C.
Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity
title Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity
title_full Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity
title_fullStr Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity
title_full_unstemmed Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity
title_short Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity
title_sort gene expression profiling in cells with enhanced γ-secretase activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739295/
https://www.ncbi.nlm.nih.gov/pubmed/19763259
http://dx.doi.org/10.1371/journal.pone.0006952
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