C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1
Alternative pre-mRNA processing is a central element of eukaryotic gene regulation. The cell frequently alters the use of alternative exons in response to physiological stimuli. Ceramides are lipid-signaling molecules composed of sphingosine and a fatty acid. Previously, water-insoluble ceramides we...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Oxford University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351148/ https://www.ncbi.nlm.nih.gov/pubmed/22210893 http://dx.doi.org/10.1093/nar/gkr1289 |
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author | Sumanasekera, Chiranthani Kelemen, Olga Beullens, Monique Aubol, Brandon E. Adams, Joseph A. Sunkara, Manjula Morris, Andrew Bollen, Mathieu Andreadis, Athena Stamm, Stefan |
author_facet | Sumanasekera, Chiranthani Kelemen, Olga Beullens, Monique Aubol, Brandon E. Adams, Joseph A. Sunkara, Manjula Morris, Andrew Bollen, Mathieu Andreadis, Athena Stamm, Stefan |
author_sort | Sumanasekera, Chiranthani |
collection | PubMed |
description | Alternative pre-mRNA processing is a central element of eukaryotic gene regulation. The cell frequently alters the use of alternative exons in response to physiological stimuli. Ceramides are lipid-signaling molecules composed of sphingosine and a fatty acid. Previously, water-insoluble ceramides were shown to change alternative splicing and decrease SR-protein phosphorylation by activating protein phosphatase-1 (PP1). To gain further mechanistical insight into ceramide-mediated alternative splicing, we analyzed the effect of C6 pyridinium ceramide (PyrCer) on alternative splice site selection. PyrCer is a water-soluble ceramide analog that is under investigation as a cancer drug. We found that PyrCer binds to the PP1 catalytic subunit and inhibits the dephosphorylation of several splicing regulatory proteins containing the evolutionarily conserved RVxF PP1-binding motif (including PSF/SFPQ, Tra2-beta1 and SF2/ASF). In contrast to natural ceramides, PyrCer promotes phosphorylation of splicing factors. Exons that are regulated by PyrCer have in common suboptimal splice sites, are unusually short and share two 4-nt motifs, GAAR and CAAG. They are dependent on PSF/SFPQ, whose phosphorylation is regulated by PyrCer. Our results indicate that lipids can influence pre-mRNA processing by regulating the phosphorylation status of specific regulatory factors, which is mediated by protein phosphatase activity. |
format | Online Article Text |
id | pubmed-3351148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-33511482012-05-14 C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1 Sumanasekera, Chiranthani Kelemen, Olga Beullens, Monique Aubol, Brandon E. Adams, Joseph A. Sunkara, Manjula Morris, Andrew Bollen, Mathieu Andreadis, Athena Stamm, Stefan Nucleic Acids Res Molecular Biology Alternative pre-mRNA processing is a central element of eukaryotic gene regulation. The cell frequently alters the use of alternative exons in response to physiological stimuli. Ceramides are lipid-signaling molecules composed of sphingosine and a fatty acid. Previously, water-insoluble ceramides were shown to change alternative splicing and decrease SR-protein phosphorylation by activating protein phosphatase-1 (PP1). To gain further mechanistical insight into ceramide-mediated alternative splicing, we analyzed the effect of C6 pyridinium ceramide (PyrCer) on alternative splice site selection. PyrCer is a water-soluble ceramide analog that is under investigation as a cancer drug. We found that PyrCer binds to the PP1 catalytic subunit and inhibits the dephosphorylation of several splicing regulatory proteins containing the evolutionarily conserved RVxF PP1-binding motif (including PSF/SFPQ, Tra2-beta1 and SF2/ASF). In contrast to natural ceramides, PyrCer promotes phosphorylation of splicing factors. Exons that are regulated by PyrCer have in common suboptimal splice sites, are unusually short and share two 4-nt motifs, GAAR and CAAG. They are dependent on PSF/SFPQ, whose phosphorylation is regulated by PyrCer. Our results indicate that lipids can influence pre-mRNA processing by regulating the phosphorylation status of specific regulatory factors, which is mediated by protein phosphatase activity. Oxford University Press 2012-05 2011-12-31 /pmc/articles/PMC3351148/ /pubmed/22210893 http://dx.doi.org/10.1093/nar/gkr1289 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Molecular Biology Sumanasekera, Chiranthani Kelemen, Olga Beullens, Monique Aubol, Brandon E. Adams, Joseph A. Sunkara, Manjula Morris, Andrew Bollen, Mathieu Andreadis, Athena Stamm, Stefan C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1 |
title | C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1 |
title_full | C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1 |
title_fullStr | C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1 |
title_full_unstemmed | C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1 |
title_short | C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1 |
title_sort | c6 pyridinium ceramide influences alternative pre-mrna splicing by inhibiting protein phosphatase-1 |
topic | Molecular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351148/ https://www.ncbi.nlm.nih.gov/pubmed/22210893 http://dx.doi.org/10.1093/nar/gkr1289 |
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