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Journal of Biochemistry 2006 139(6):1083-1088; doi:10.1093/jb/mvj122
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© 2006 The Japanese Biochemical Society.

Regular Paper

Proinsulin C-Peptide Stimulates a PKC/I{kappa}B/NF-{kappa}B Signaling Pathway to Activate COX-2 Gene Transcription in Swiss 3T3 Fibroblasts

Masashi Kitazawa1, Yasutaka Shibata2, Seiichi Hashimoto2, Yasushi Ohizumi1,3 and Tohru Yamakuni1,*

1 Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578; 2 Molecular Medicine Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585; and 3 Yokohama College of Pharmacy, 601 Matano-cho, Tozuka-ku, Yokohama 245-0066

* To whom correspondence should be addressed. Tel: +81-22-795-6852, Fax: +81-22-795-6850, E-mail: yamakuni{at}mail.pharm.tohoku.ac.jp

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 {kappa}B (I{kappa}B)/NF-{kappa}B–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-{kappa}B (NF-{kappa}B) inhibitor, accompanied by increased phosphorylation and degradation of I{kappa}B. These results suggest that C-peptide stimulates the transcription of inflammatory genes via activation of a PKC/I{kappa}B/NF-{kappa}B signaling pathway.


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