Ceramide synergizes with phorbol ester or okadaic acid to induce IkappaB degradation.
Ceramide is a lipid second messenger which is generated in response to stimulation of a number of surface receptors, treatment with chemotherapeutic agents, or ionising radiation. Depending on the target cell, ceramide induces diverse biological responses including apoptosis, cell-cycle arrest, differentiation, and also proliferation. We studied the effect of ceramide on the degradation of IkappaB, the cytoplasmic inhibitor of the transcription factor NF-kappaB. We show that ceramide treatment results in reduced levels of phosphorylated IkappaBalpha and degradation of both IkappaBalpha and IkappaBbeta. Ceramide synergised with okadaic acid (OA), a compound which interferes with the protein phosphatase 2A-controlled component of the NF-kappaB activation pathway, enhancing OA-induced IkappaB degradation. Ceramide also synergised with phorbol 12-myristate 13-acetate, which mimics protein kinase C activation. Finally, we show that the synergistic effect of ceramide with OA or phorbol ester can be observed in primary lymph node T-cells as well as in transformed T-cells.
Fernandez
P C
PC
Molecular Pathology, University of Berne, Länggass-strasse 122, Berne, CH-3012, Switzerland.
Dobbelaere
D A
DA
D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000008:administration & dosage* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D019319:Okadaic Acid / Q000008:administration & dosage*; D011493:Protein Kinase C / Q000378:metabolism; D015290:Second Messenger Systems; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage*; D016797:Theileria parva / Q000472:pathogenicity
D002518:Ceramides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; D011493:Protein Kinase C; D013108:Sphingomyelin Phosphodiesterase; D013755:Tetradecanoylphorbol Acetate