Inhibition of protein prenylation down-regulates signalling by inflammatory mediators in human keratinocytes.
Several inflammatory mediators have been shown to activate phospholipase C in human keratinocytes via GTP-binding protein-coupled receptors. Since GTP-binding proteins are prenylated proteins, we have examined the role of prenylation in signal transduction in HaCaT keratinocytes. Indirect inhibition of prenylation with the HMG CoA reductase inhibitors fluvastatin or compactin decreased bradykinin-stimulated inositol 1,4,5-triphosphate generation. This effect was abolished by mevalonic acid but not by serum, indicating a requirement for a non-sterol metabolite for signal generation. The BK response was also inhibited by zaragozic acids B and C, known inhibitors of prenyl protein transferases. These results suggest that protein prenylation may be a novel therapeutic target in dermatological conditions where an up-regulation of the inositol lipid pathway has been demonstrated.
Alaei
P
P
General Dermatology Department, Sandoz Research Institute, Vienna, Austria.
MacNulty
E E
EE
Ryder
N S
NS
D000255:Adenosine Triphosphate / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D017368:Protein Prenylation; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D001596:Benzylamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D010972:Platelet Activating Factor; D013876:Thiophenes; C066059:NB 598; C079089:zaragozic acid B; D000077340:Fluvastatin; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D013917:Thrombin; D008798:Mevalonic Acid; D001920:Bradykinin