Proinsulin C-peptide stimulates a PKC/IkappaB/NF-kappaB signaling pathway to activate COX-2 gene transcription in Swiss 3T3 fibroblasts.
Proinsulin C-peptide causes multiple molecular and physiological effects, and improves renal and neuronal dysfunction in patients with diabetes. However, whether C-peptide controls the inhibitor kappaB (IkappaB)/NF-kappaB-dependent transcription of genes, including inflammatory genes is unknown. Here we showed that 1 nM C-peptide increased the expression of cyclooxygenase-2 (COX-2) mRNA and its protein in Swiss 3T3 fibroblasts. Consistently, C-peptide enhanced COX-2 gene promoter-activity, which was inhibited by GF109203X and Go6976, specific PKC inhibitors, and BAY11-7082, a specific nuclear factor-kappaB (NF-kappaB) inhibitor, accompanied by increased phosphorylation and degradation of IkappaB. These results suggest that C-peptide stimulates the transcription of inflammatory genes via activation of a PKC/IkappaB/NF-kappaB signaling pathway.
Kitazawa
Masashi
M
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578.
Shibata
Yasutaka
Y
Hashimoto
Seiichi
S
Ohizumi
Yasushi
Y
Yamakuni
Tohru
T
D000818:Animals; D015153:Blotting, Western; D002096:C-Peptide / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D011384:Proinsulin / Q000737:chemistry; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D041701:Swiss 3T3 Cells; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D002096:C-Peptide; D002227:Carbazoles; D020672:I-kappa B Proteins; D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D009570:Nitriles; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D013450:Sulfones; C081021:Go 6976; D011384:Proinsulin; D008156:Luciferases; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; C070515:bisindolylmaleimide I