Ceramide-1-phosphate promotes cell survival through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway.
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.
Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of the Basque Country, P.O. Box 644, 48080 Bilbao, Spain. gbpgomua@lg.ehu.es
Antonio
A
Gómez-Muñoz
Jennifer Y
JY
Kong
Kuljit
K
Parhar
Shih Wei
SW
Wang
Patricia
P
Gangoiti
Mónica
M
González
Sharlene
S
Eivemark
Bill
B
Salh
Vincent
V
Duronio
Urs P
UP
Steinbrecher
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D002470:Cell Survival; D002518:Ceramides / Q000494:pharmacology / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein
D002518:Ceramides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse; C065576:ceramide 1-phosphate