Abstract
In this report, we show for the first time that ceramide-1-phosphate (C1P) stimulates the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway, which is a major mechanism whereby growth factors promote cell survival. Also, C1P induced IkappaB phosphorylation, and enhanced the DNA binding activity of the transcription factor NF-kappaB. Apoptotic macrophages showed a marked reduction of Bcl-X(L) levels, and this was prevented by C1P. These findings suggest that C1P blocks apoptosis, at least in part, by stimulating the PI3-K/PKB/NF-kappaB pathway and maintaining the production of antiapoptotic Bcl-X(L). Based on these and our previous observations, we propose a working model for C1P in which inhibition of acid sphingomyelinase and the subsequent decrease in ceramide levels would allow cell signaling through stimulation of the PI3-K/PKB pathway to promote cell survival.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Bone Marrow Cells / metabolism
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Cell Survival
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Ceramides / pharmacology
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Ceramides / physiology*
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DNA-Binding Proteins / metabolism
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Female
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I-kappa B Proteins / metabolism
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Macrophages / metabolism
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Mice
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Up-Regulation
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bcl-X Protein
Substances
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Bcl2l1 protein, mouse
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Ceramides
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DNA-Binding Proteins
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I-kappa B Proteins
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NF-kappa B
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-X Protein
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ceramide 1-phosphate
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt