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Effects of N,N‐Dimethylsphingosine on Sphingosine Kinase
Author(s) -
Yu JiaDe,
Gude David,
Paugh Steven William,
Alvarez Sergio,
Milstien Sheldon,
Spiegel Sarah
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a484-c
Subject(s) - sphingosine , sphingosine kinase , chemistry , sphingosine kinase 1 , sphingosine 1 phosphate , biochemistry , receptor
Sphingosine‐1‐phosphate (S1P) is a bioactive lipid that regulates a myriad of important cellular processes including growth, survival, cytoskeleton rearrangements, motility, angiogenesis, and immunity. There are two distinct sphingosine kinase isoforms, SphK1 and SphK2, which produce S1P. N,N‐dimethylsphingosine (DMS), a methyl derivative of sphingosine, is a potent inhibitor of both sphingosine kinases. By inhibiting SphK activity, DMS alters the sphingolipid rheostat shifting the balance towards the pro‐apoptotic sphingosine and ceramide, and away from the anti‐apoptotic S1P. Though previous experiments show that DMS reduces S1P levels in cells, surprisingly, we have now found that treatment of U937 leukemia cells or Jurkat T lymphoma cells with DMS causes SphK1 protein levels to be drastically increased 24 hours after treatment. In addition, western blotting with a specific anti‐SphK1 antibody revealed that the DMS effect was dose‐dependent. Yet SphK1 activity remained markedly reduced. Preliminary results suggest that the increase in SphK1 is independent of both translation and transcription as treatment with actinomycin D (a transcription inhibitor) or cycloheximide (a translation inhibitor) did not prevent DMS‐induced increases in SphK1. Experiments are now underway to determine how DMS increases SphK1 levels.