C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1
Authors
Sumanasekera, ChiranthaniKelemen, Olga
Beullens, Monique
Aubol, Brandon E.
Adams, Joseph A.
Sunkara, Manjula
Morris, Andrew
Bollen, Mathieu
Andreadis, Athena
Stamm, Stefan
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2012-05-01Keywords
CeramidesAlternative Splicing
RNA Precursors
Protein Phosphatase 1
Enzyme Inhibitors
Pyridinium Compounds
Cell Biology
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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.Source
Nucleic Acids Res. 2012 May;40(9):4025-39. Epub 2011 Dec 30. doi: 10.1093/nar/gkr1289. Link to article on publisher's website
DOI
10.1093/nar/gkr1289Permanent Link to this Item
http://hdl.handle.net/20.500.14038/25681PubMed ID
22210893Related Resources
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Copyright The Author(s) 2011. Published by Oxford University Press. 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.
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http://creativecommons.org/licenses/by-nc/3.0/ae974a485f413a2113503eed53cd6c53
10.1093/nar/gkr1289
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Except where otherwise noted, this item's license is described as <p>Copyright The Author(s) 2011. Published by Oxford University Press. 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.</p>