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...

Descripción completa

Detalles Bibliográficos
Autores principales: Sumanasekera, Chiranthani, Kelemen, Olga, Beullens, Monique, Aubol, Brandon E., Adams, Joseph A., Sunkara, Manjula, Morris, Andrew, Bollen, Mathieu, Andreadis, Athena, Stamm, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2012
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
_version_ 1782232735189827584
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
work_keys_str_mv AT sumanasekerachiranthani c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT kelemenolga c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT beullensmonique c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT aubolbrandone c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT adamsjosepha c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT sunkaramanjula c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT morrisandrew c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT bollenmathieu c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT andreadisathena c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1
AT stammstefan c6pyridiniumceramideinfluencesalternativepremrnasplicingbyinhibitingproteinphosphatase1