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Title: C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1
Authors: Sumanasekera, Chiranthani ×
Kelemen, Olga
Beullens, Monique
Aubol, Brandon E
Adams, Joseph A
Sunkara, Manjula
Morris, Andrew
Bollen, Mathieu
Andreadis, Athena
Stamm, Stefan #
Issue Date: 2012
Publisher: Oxford University Press
Series Title: Nucleic Acids Research vol:40 pages:4025-4039
Abstract: 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.
URI: 
ISSN: 0305-1048
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Biosignaling & Therapeutics
× corresponding author
# (joint) last author

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